Scientists have recently discovered that they also play a role in responding to nerve activity and modulating communication between nerve cells.
When glia do not function properly, the result can be disastrous—most brain tumors are caused by mutations in glia. There are several different types of glia with different functions, two of which are shown in Figure Astrocytes , shown in Figure They provide nutrients and other substances to neurons, regulate the concentrations of ions and chemicals in the extracellular fluid, and provide structural support for synapses. Astrocytes also form the blood-brain barrier—a structure that blocks entrance of toxic substances into the brain.
Astrocytes, in particular, have been shown through calcium imaging experiments to become active in response to nerve activity, transmit calcium waves between astrocytes, and modulate the activity of surrounding synapses. Satellite glia provide nutrients and structural support for neurons in the PNS. Microglia scavenge and degrade dead cells and protect the brain from invading microorganisms. Oligodendrocytes , shown in Figure One axon can be myelinated by several oligodendrocytes, and one oligodendrocyte can provide myelin for multiple neurons.
This is distinctive from the PNS where a single Schwann cell provides myelin for only one axon as the entire Schwann cell surrounds the axon. Radial glia serve as scaffolds for developing neurons as they migrate to their end destinations. Ependymal cells line fluid-filled ventricles of the brain and the central canal of the spinal cord. They are involved in the production of cerebrospinal fluid, which serves as a cushion for the brain, moves the fluid between the spinal cord and the brain, and is a component for the choroid plexus.
The nervous system is made up of neurons and glia. Neurons are specialized cells that are capable of sending electrical as well as chemical signals. Most neurons contain dendrites, which receive these signals, and axons that send signals to other neurons or tissues. There are four main types of neurons: unipolar, bipolar, multipolar, and pseudounipolar neurons.
Glia are non-neuronal cells in the nervous system that support neuronal development and signaling. There are several types of glia that serve different functions. Skip to content Chapter The Nervous System. Learning Objectives By the end of this section, you will be able to: List and describe the functions of the structural components of a neuron List and describe the four main types of neurons Compare the functions of different types of glial cells.
Concept in Action. Parts of a Neuron. Neurons contain organelles common to many other cells, such as a nucleus and mitochondria. They also have more specialized structures, including dendrites and axons.
The soma is the cell body of a nerve cell. Myelin sheath provides an insulating layer to the dendrites. The astrocytic endfeet ensheath the vascular tube and help to regulate ion and water regulation Abbott et al. Aquaporin-4 is an astroglial water channel that regulates perivascular fluid and solute movement through the glymphatic system, a unique exchange between perivascular cerebrospinal fluid CSF and interstitial fluid present in the CNS Iliff et al.
Using this system, the brain can regulate fluid flow throughout the CNS and aid in clearance of toxins. In addition, the connection between neurons and blood vessels allows astrocytes to relay signals regarding blood flow Hamilton and Attwell, as well as controlling brain water content Zlokovic, Of the approximately 11 distinct phenotypes of astrocytes, 8 are involved in interactions with blood vessels Reichenbach and Wolburg, ; Abbott et al. Astrocytes and endothelial cells have a symbiotic relation.
Astrocytes secrete a range of chemical factors, including various growth factors that induce aspects of the BBB phenotype in endothelial cells in vitro and likely in vivo while endothelial cells aid in astrocytic differentiation Mi et al. Astrocytic end feet are polarized and guided to cerebral vessel walls by pericytes Armulik et al. Pericytes sit on the abluminal surface of the endothelial cell and are embedded in the vascular basement membrane and are physically connected to brain endothelial cells by way of gap junctions and peg and socket arrangements Miller and Sims, Pericytes help to maintain and stabilize the monolayer of brain endothelial cells by regulating angiogenesis and depositing extracellular matrix.
Pericytes are essential for development of tight junctions, including in the development of barrier functions in utero Daneman et al. In addition, there is cross talk from the brain endothelial cell to the pericyte on pericyte proliferation and migration. CNS pericytes also have distinct properties from their peripheral counterparts. The endothelial:pericyte ratio is much greater in the CNS, estimated to be about in mice Bonkowski et al.
Pericytes can regulate blood flow in response to neural activity Armulik et al. These cell types brain endothelial cells, neurons, astrocytes, and pericytes communicate with one another to not only help form the BBB but also to regulate its structure and function. As touched on above, these cells can communicate with secretory factors in addition to changes in fluid movement and water channels.
Interruptions in signaling within one cell type could have detrimental effects in all cell types. For example, pericyte loss has been shown to occur in some animal models of peripheral insulin resistance Price et al. Loss of pericytes can lead to BBB breakdown, causing a dysfunction in the transport regulation of blood-to-brain and brain-to-blood factors.
In the next section, we will describe the role of the insulin receptor in each of these cell types and speculate how insulin resistance in one cell type might adversely affect some of the other BBB cell types. There is not a cell type in the CNS that we are aware of that does not express the insulin receptor. In mice, the expression of the insulin receptor gene is most abundant in endothelial cells, about two times greater than astrocytes, with neurons falling in close behind in terms of RNA expression levels 1 Zhang et al.
This same expression pattern was not observed in samples from human tissue Zhang et al. Instead, expression of the insulin receptor is more evenly distributed between the cell types. Insulin interacts with receptors on neurons and glial cells Unger et al.
However, until recently, the ability to detect these two isoforms by immunological methods in vivo in different cell types has been a challenge. With the advances in single cell RNA sequencing Ofengeim et al. The insulin receptor can also form heterodimers with the IGF-1 receptor and can have varying post-translational modifications leading to further diversity of insulin action Wozniak et al. Figure 1. Summary of the role of insulin receptor signaling in various cells of the BBB.
Cell types are listed here with the role of insulin receptor signaling listed in bullet points. Insulin gray circles must first cross barrier cells in order to activate insulin receptors gray receptor in the CNS located on neurons, astrocytes, and pericytes. Figure 1 summarizes the role of the insulin receptor on each BBB cell type discussed in this review. Various groups have utilized Cre-loxP-mediated recombination Gu et al. We have included a table listing the studies generating and utilizing some of these CNS insulin receptor knock-out models Table 1.
Table 1. The original study introducing these mice investigated the role of the endothelial cell in regulating vascular tone and peripheral insulin resistance.
Abnormal architecture of capillary integrity could not be detected in brain Vicent et al. Using a euglycemic-hyperinsulinemic clamp, the authors found endothelial cell insulin receptors do not play a role in the access of insulin to peripheral metabolically active tissues but did not investigate brain. Loss of the endothelial insulin receptor resulted in decreased levels of eNOS, an important regulator of vascular tone which could affect exposure to various circulatory factors.
Indeed, the cerebrovascular response to insulin appears to be biphasic with vasoconstriction at low doses and vasodilation at higher doses Katakam et al. Vascular integrity of the BBB was later investigated in these mice Kondo et al. Levels of ZO-1, a tight junction protein, were unchanged in addition to levels of astrocytes, as measured by GFAP staining. These differences between the two models could be due to regional regulation of tight junction proteins by the insulin receptor.
Using the EndoIRKO model, it was demonstrated insulin receptors on brain endothelial cells control the kinetics of insulin signaling in certain regions of the brain, such as the hippocampus and hypothalamus, but not the olfactory bulb Konishi et al.
The results from these two models suggests the insulin receptor in endothelial cells has a regional effect in relaying insulin signaling to other cell types in addition to maintaining the BBB structure by regulating tight junction protein expression. In addition to the genetically modified mouse models, some groups have utilized a selective inhibitor of the insulin receptor, S, in vitro to investigate the role of the brain endothelial cell insulin receptor.
This inhibitor has high affinity and selectivity, especially over the IGF-1 receptor Schaffer et al. Insulin binding was decreased with S treatment Hersom et al.
It was also shown that while the downstream insulin receptor signaling mediator PI3K was inhibited, insulin uptake was not altered Gray et al.
On the other hand, high-fat diet decreased insulin uptake, yet insulin receptor signaling was unaltered Gray et al. These data suggest a disconnect between insulin receptor signaling and insulin transport across the endothelial cell which we will discuss later. Therefore, it is important to consider the effects of insulin at the BBB when administered luminally versus abluminally. Insulin signaling in the CNS is important for promoting neuronal survival and regulating key processes involved in learning and memory synapse density, plasticity, and connectivity.
Insulin in the brain is more closely linked to its ancestral roles by acting more as a growth factor rather than acting as a metabolite to regulate glucose uptake as occurs in the periphery Banks et al. Peripheral injection of 1 mU insulin increased cerebral insulin signaling within 5 min, which was localized to the plasma membrane of a subset of neurons Freude et al.
The loss of the insulin receptor leads to impaired peripheral metabolism as the mice aged. NIRKO mice exhibit decreased dopamine signaling and impairments in mitochondrial function Kleinridders et al. In Xenopus tadpoles, loss of the insulin receptor specifically in tectal neurons reduces synapse density, decreases activation, and alters morphology Chiu et al.
In addition, the insulin receptor was not required for neuronal survival in vivo Bruning et al. While this data is not in line with other reports on the mechanism of insulin in the CNS to promote neuronal survival and play a role in memory, it is likely compensation has occurred due to complete loss of the insulin receptor throughout the brain for the entire life of the animal, as previously suggested Grillo et al.
If the insulin receptor is downregulated specifically in the hippocampus of adult rats using a lentivirus, long-term memory is impaired Grillo et al. It is important to note that there were no metabolic or endocrine changes with specific knock-down in the hippocampus despite prior work by this group showing metabolic changes when targeted to the hypothalamus Grillo et al.
These differences when the insulin receptor is targeted in specific regions highlight the need to further investigate the role of the insulin receptor in a regional context. In addition, the insulin stimulated phosphorylation of tau was at a site demonstrated to form tangles Kimura et al.
This effect of insulin on tau phosphorylation seems to be time dependent based on studies in vitro Lesort et al. These data show that insulin receptor signaling can impact tau phosphorylation given the right time and environment.
While numerous groups have shown insulin can affect tau phosphorylation, there are fewer studies suggesting tau can regulate insulin signaling. Tau pathology triggers insulin accumulation and oligomerization. Inhibition of tau phosphorylation using okadaic acid decreased insulin receptor expression levels in neurons, and this was dependent on the presence of extracellular insulin.
In addition, neurons with increased tau hyperphosphorylation have enhanced insulin uptake Rodriguez-Rodriguez et al. Indeed, activation of insulin receptor signaling enhances IDE expression in neurons Zhao et al. Because these studies were completed with purified components i. Primary human astrocytes express the insulin receptor and downstream signaling mediators and are responsive to insulin by altering glycogen synthesis and cell proliferation Heni et al.
Astrocytes can respond to insulin concentrations as low as 1 nM, concentrations that are commonly exceeded in the blood of healthy humans following feeding.
These data suggest that even if CSF insulin levels are low, astrocytes might be exposed to comparable blood levels due to their close contact with blood vessels. Specifically in astrocytes, insulin receptor gene expression increases with age in the mouse Clarke et al.
Interestingly, it is not until the age of 2 years that mouse hippocampal astrocytes reach their peak in insulin receptor gene expression. Astrocytes are one type of brain cell that have the ability to proliferate in adults. Astrocyte cell numbers increase after addition of insulin to the culture medium but high glucose inhibits astrocyte proliferation Li et al. Astrocytes predominantly express the insulin receptor-B isoform Garwood et al.
While the loss of insulin receptor signaling in neurons has been studied for decades, the loss in astrocytes has only recently begun to be investigated. Postnatal loss of the insulin receptor in astrocytes affects morphology, circuit connectivity, and mitochondrial function Garcia-Caceres et al.
Insulin signaling in astrocytes also plays a role in potentiating release of dopamine and ATP Cai et al. In an insulin-deficient mouse model of diabetes, astrocytes retract at the BBB Salameh et al. This ultimately leads to a disruption of the BBB, both structurally and via permeability to sucrose. BBB permeability in models lacking the astrocytic insulin receptor has not been investigated. The loss of the insulin receptor reduces activation of neurons by glucose, which ultimately alters glucose transport across the BBB Garcia-Caceres et al.
GLUT1 is more abundantly expressed in astrocytes compared to brain endothelial cells Simpson et al. Astrocytes are a major source of apolipoprotein E apoE in the brain Kim et al. The secretion of apoE4 from astrocytes led to impaired barrier function in vitro Nishitsuji et al. This data suggests insulin can regulate multiple aspects of astrocyte function, which can ultimately affect neuronal plasticity and activity in the brain. Loss of the insulin receptor present in astrocytes or impairment in insulin response could weaken this clearance.
Human pericytes express the insulin receptor James and Cotlier, yet the alpha subunit is undetectable in cultured human brain pericytes Rensink et al.
Insulin does not stimulate glucose uptake in cultured human brain pericytes Rensink et al. It has also been shown that cell proliferation is enhanced more in pericytes due to insulin exposure compared to endothelial cells King et al.
Most studies investigating the role of the insulin receptor in pericytes have been done on cells isolated from bovine retinal capillaries Escudero et al. Insulin can induce hyperpolarization of pericytes through calcium sensitive potassium channels Berweck et al. Pericyte insulin signaling reduces endothelial cell death Kobayashi and Puro, Pericyte-derived media, but not astrocyte-derived media, was able to increase the insulin stimulated phosphorylation of Akt and insulin receptor in a hypothalamic neuronal cell line, suggesting pericytes can increase insulin sensitivity in these neurons Takahashi et al.
A mouse model with a pericyte specific knockout of the insulin receptor was used to investigate the role of insulin signaling in retinal angiogenesis Warmke et al.
Early on postnatal day 5 , retinas are hypervascularized in the knockout mice, which did not persist into adulthood. Changes in insulin signaling, pericyte function, or BBB changes were not reported in this abstract. Even though the loss of the insulin receptor in specific cell types of the NVU has not been exhaustively investigated within the last two decades, there is still much to learn from these various models.
For example, it is largely unknown what combinatorial effects might occur due to the loss of the insulin receptor in multiple cell types. Second, it is largely unknown how the loss of the insulin receptor in one cell type impacts another cell type. The use of the novel ex vivo technique utilizing BBB organoids Bergmann et al. Third, the regional effect of the insulin receptor has hardly been studied. More studies utilizing targeted knock-down of the insulin receptor should be performed in order to better understand the specific role of the insulin receptor in regions dedicated to different processes.
Another way to get at this question would be to utilize optogenetics to inhibit the insulin receptor in certain sub-populations of cell types to determine the downstream impact. Lastly, something that has not really been touched on here but is important to consider is the location of the insulin receptor within the cell types. It has been shown in cultured hippocampal neurons that the insulin receptor is present primarily in the postsynaptic density Abbott et al. However, the localization of the insulin receptor in other cell types in other regions has largely been uninvestigated.
Investigators have been examining the transport of insulin into the brain since when it was observed that minimal amounts of radioactively labeled insulin appeared in brain tissue following intravenous or subcutaneous injection Haugaard et al. It was later more definitively shown that serum insulin appeared in CSF in dogs following insulin infusion Margolis and Altszuler, Intravenously administered insulin is detected in brain within 1 min Banks and Kastin, ; Banks et al.
Transport of insulin across the BBB has been validated many times using various techniques including perfusions Schwartz et al. The transporter for insulin at the BBB is not static but rather a dynamic protein regulated by the current physiological state of the body. In fact, during a time in which the brain is developing the greatest, the neonatal period, insulin transport across the BBB and binding to the brain endothelial cells is increased compared to weanling and adult periods Frank et al.
CSF and brain insulin levels are also significantly greater in the neonatal period. Insulin binding to brain capillaries is highest in the newborn rabbits compared to adults suggesting the presence of higher levels of insulin binding sites Frank et al. These discrepancies between neonates and adults is likely due to the mitogenic nature of insulin action in the CNS rather than the metabolic role. Other physiological regulators of insulin transport that relate to insulin resistance are discussed in the next section.
We also know the rate of transport of insulin BBB transport varies between brain regions based on requirement. Insulin transport is not flow dependent like glucose. For some time now, it has been thought the insulin receptor present on the brain endothelial cell mediates this transport.
This concept has some validity to it as regions in which insulin receptor expression is greatest, such as the olfactory bulb Schulingkamp et al. However, what is not necessarily taken into consideration is the amount of insulin receptor present on neurons, astrocytes, pericytes, and other CNS cell types in these brain regions versus the levels present on brain endothelial cells.
With the increasing use of single-cell RNA sequencing, we are beginning to learn more about the expression pattern of the insulin receptor in different CNS cell types Zhang et al. In addition, variable cerebral blood circulation, diverse capillary density in the brain, or other factors, such as expression levels of insulin transport protein mediators could also drive the regional transport differences. Studies using in vitro transport models Gray et al.
However, we have recently shown using dynamic, pharmacokinetic in vivo techniques in a mouse model lacking the insulin receptor in brain endothelial cells and use of pharmacological inhibition of the insulin receptor, insulin transport across the BBB is unchanged Rhea et al.
It was also confirmed by a separate group using primary brain endothelial cells and capillaries from bovine, rat, and mouse that inhibition of the insulin receptor did not affect transport Hersom et al. Regional expression of the insulin transporter could be responsible for the regional transport differences.
The rationale that the insulin transporter is separate from the insulin receptor is not far-fetched. An important signaling peptide such as insulin should have a protein that it can bind to and elicit an internal signaling cascade in addition to having another protein that can transport this signaling peptide to other areas necessary for signaling Figure 2. In addition, these separate proteins should be able to be regulated differently, depending on the physiological necessity at any given time.
For example, insulin receptor signaling in the brain endothelial cell relays a signal to neurons Konishi et al. In addition, insulin signaling in endothelial cells is a vasoregulator Vicent et al. Since endothelial cells create a barrier to other cells within organs, it can be speculated these cells would also contain a transporter to independently get insulin to other cell types in order to act physiologically there.
Insulin transport is not related to amino acid transport, the p -glycoprotein system, a slow calcium channel, alpha-adrenergic action, or growth hormone, somatostatin, glucagon, or leptin transport Frank et al. However, this study used about a fold excess amount of IGF-1 so the physiological relevance on insulin transport is still unclear. Based on the lack of competitive inhibition with most substrates tested and the data showing changes in insulin transport under various physiological conditions, it is likely that the insulin transporter is rather specific for insulin but is regulated in an allosteric manner.
Figure 2. Glial cells of the a central nervous system include oligodendrocytes, astrocytes, ependymal cells, and microglial cells. Oligodendrocytes form the myelin sheath around axons. Astrocytes provide nutrients to neurons, maintain their extracellular environment, and provide structural support. Microglia scavenge pathogens and dead cells. Ependymal cells produce cerebrospinal fluid that cushions the neurons. Glial cells of the b peripheral nervous system include Schwann cells, which form the myelin sheath, and satellite cells, which provide nutrients and structural support to neurons.
Astrocytes , shown in Figure 2a make contact with both capillaries and neurons in the CNS. They provide nutrients and other substances to neurons, regulate the concentrations of ions and chemicals in the extracellular fluid, and provide structural support for synapses. Astrocytes also form the blood-brain barrier—a structure that blocks entrance of toxic substances into the brain. Natural Selection 3. Classification 4. Cladistics 6: Human Physiology 1. Digestion 2. The Blood System 3. Disease Defences 4.
Gas Exchange 5. Homeostasis Higher Level 7: Nucleic Acids 1. DNA Structure 2. Transcription 3. Translation 8: Metabolism 1. Metabolism 2. Cell Respiration 3.
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