Impact of hypoxia on the A review

Authors: Guan Lu, Ge Rili, Ma Shuang

Abstract

Oxygen is the most abundant chemical substance and is a basic material for human activities. A decline in oxygen concentration affects many physiological processes in the body, leading to pathological changes and even the occurrence of diseases. Therefore, an increasing number of studies have focused on the pathological state of hypoxia. The hippocampus is the most sensitive tissue to oxygen in the brain. The reduction in oxygen concentration affects the morphology and functioning of the hippocampus, including a decline in learning and memory, immunity, and energy metabolism, causing great problems to people’s physical and mental health. To keep people healthy in hypoxic environments, adapt to hypoxic environments, and avoid diseases, it is necessary to review the morphology and function of the hippocampus, as well as the effect of oxygen on the hippocampus.

1. Introduction

Hypoxia can be divided into acute, chronic, persistent, intermittent, chemical, and postpartum hypoxia based on the cause of the disease. Hypoxic preconditioning and treatment can also be used to treat diseases. Hypoxia is a major pathological factor in brain injury.^[1]^ The hippocampus is the most sensitive tissue in the brain to hypoxia, and hypoxia affects attention, executive function, learning and memory, speed of memory processing, declarative memory, and other functions of the hippocampal tissue.^[2,3]^ Different degrees and types of hypoxia have different effects on the hippocampus. Some studies have proposed that transient hypoxia can cause structural changes and dysfunction of neurons, including the shortening and thinning of dendrites and weakening of excitatory synaptic transmission strength, which affect brain development.^[4]^ This article reviews the effects of hypoxia on hippocampal learning and memory, neuronal development and angiogenesis, synaptic plasticity, inflammation and immunity, oxidative stress, autophagy, apoptosis, and energy metabolism.

2. Morphology and function of hippocampus

The hippocampus, also known as the hippocampal gyrus, hippocampal area, or brain hippocampus, is named for its structural shape, which is similar to that of the hippocampus. Located between the cerebral colliculus and medial temporal lobe, the hippocampal formation is composed of the dentate gyrus and inferior torus of the hippocampus and its adjacent temporal lobe, which can be divided into CA1, CA2, CA3, and DG areas, which belong to a part of the limbic system (Fig. 1).

Currently, the role of the hippocampus remains controversial, but most scientists believe that the hippocampus has episodic or autobiographical memories. The hippocampus is not only involved in the formation of new memories but also in learning and emotion. There are also some fixed-point cells in the hippocampus, which are involved in the storage and processing of spatial information. When information enters the hippocampus, it first passes through the CA3 area, then the CA1 area, and then reaches the subthalamus.

Damage to the hippocampus can affect memories and the ability to form new memories. Spatial memory is the ability to remember direction, position, and orientation. Damage to the left hippocampus affects the memory of language information, whereas damage to the right hippocampus affects the memory of visual information.

3. Effects of hypoxia

3.1. Learning and memory and cognitive function

Hypoxia impairs the cognitive and motor abilities of mice by affecting hippocampal mitochondrial oxidative phosphorylation but has no significant effect on the morphology and structure of the brain in mice.^[5]^ The learning and memory abilities of rats were also affected by hypoxia, which showed that the escape latency of rats was prolonged, damage to hippocampal neurons was reduced, and learning and memory abilities were restored to some extent. In addition, hypoxia-induced hippocampal atrophy, memory impairment, and decreased motor responses in rats.^[6]^ Hypoxia promotes tau phosphorylation through the extracellular regulated protein kinases (ERK) signaling pathway, which affects learning and memory.^[7]^ Hypoxia promotes the expression of matrix metalloprotein 9 in the rat hippocampus and affects passive avoidance learning abilities in rats.^[8]^ Hypoxia affects horizontal movement and carding activity in rats. Rats show differences in different areas of hypoxia, and the results also differ according to sex.^[1]^ In a hypoxic environment of 4010 m in the hippocampus, the latency and number of crossings of the salidroside platform in mice were reduced, the damage to hippocampal neurons was alleviated, the expression of apoptotic proteins was reduced, and the learning and memory ability was improved.^[9]^

Acute high-altitude hypoxic exposure can change the morphology of vertebral neurons in the hippocampal CA1 area, affect the expression of proteins in the hippocampus, and lead to cognitive dysfunction.^[10]^ Under continuous hypoxia, the dendritic spines in the hippocampal CA1 region of mice decreased, synaptic plasticity decreased, escape latency was prolonged, and spatial learning and memory abilities decreased.^[11]^ After acute high-altitude exposure for 7 days, mice showed obvious memory impairment, hippocampal neuron pyknosis, and increased expression of apoptotic proteins.^[12]^ Exposure to acute hypobaric hypoxia exposure can impair cognitive function in rats. Ginkgolide B intervention may regulate hippocampal neuronal calcium homeostasis by regulating the hippocampal Calcium/calmodulin-dependent protein kinase type Ⅱ signaling pathway, alleviating hippocampal neuronal injury, improving learning and spatial memory in rats, and alleviating cognitive dysfunction.^[13]^

The effects of hypobaric hypoxia on the nervous system have become increasingly serious over the years. When exposed to hypoxia for 2 days, the dendritic length of pyramidal cells decreased and was the most serious on the 7th day. One of the mechanisms underlying the hippocampal-dependent spatial learning decline is dendritic cell atrophy.^[14]^ Single-simulated hypobaric hypoxia is beneficial to the behavior of mice by activating mild stress in the mitochondria.^[15]^ Hypobaric hypoxia impairs the cognitive, motor coordination, and spatial memory ability of rats by inhibiting the synthesis of catecholamine,^[16]^ also available via peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha/fibronectin type III domain-containing protein 5/brain-derived neurotrophic factor (BDNF) signaling pathway causes damage to hippocampal mitochondria and synapses, leading to memory impairment.^[17]^ Hypobaric hypoxia can improve oxidative stress and synaptic plasticity by activating the Notch pathway, which can cause learning and memory impairment and reduce the cognitive index of new objects in mice.^[18]^

Chronic exposure to hypoxia at high altitudes results in a reduction in hippocampal gray matter volume, impaired learning and memory ability, and anxiety-like behavior in rats.^[19]^ Chronic intermittent hypoxia leads to anxiety-like behavior in mice, which is related to the compensatory increase in NMDA receptor 2B, ERK, and the synaptic plasticity of neurons.^[20]^ Chronic intermittent hypoxia can reduce synaptic plasticity in hippocampal neurons by activating adenosine A2AR, resulting in spatial memory impairment in mice. Knocking out or inhibiting adenosine A2AR improves synaptic plasticity in hippocampal neurons and reduces spatial memory impairment in mice.^[21]^ Chronic intermittent hypoxia can promote the expression of ERK1/2 in the hippocampus, reduce the volume of hippocampal neurons, pyknosis of nucleus, cause cognitive dysfunction, increase the escape latency, and reduce the number of crossing the platform. Chronic intermittent hypoxia promotes the expression of inflammatory factors in the hippocampus, leading to microglia damage and cognitive decline.^[22]^ Intermittent hypoxia caused the loss of NMDA receptor-dependent long-term enhancement and the increase of reactive oxygen species (ROS) in the hippocampal CA1 region, resulting in the decrease of hippocampal synaptic plasticity and the impairment of spatial memory ability, which was related to hypoxia-inducible factor (HIF-1) alpha (HIF-1α) dependent redox state changes.^[23]^ Intermittent hypoxia through the nuclear factor kappa-B (NF-κB) signaling pathway causes neuronal apoptosis, affects cognitive function of mice, and prolongs the latency of target quadrant in mice.^[24]^ Intermittent hypoxia therapy promotes tau phosphorylation through the mammalian target of rapamycin (mTOR) signaling pathway, reduces the expression of glutamate-relevant proteins in the hippocampus, and improves cognitive function in mice.^[25]^ Intermittent hypoxia promotes oxidative stress in rat hippocampal neurons and affects learning and memory. This situation can be improved using the total glycosides of Cistanche deserticola.^[26]^

Prenatal hypoxia interferes with hippocampal CA3-CA1 synaptic transmission and reduces long-term potentiation, which may be caused by the inhibition of GluN2B protein expression, ultimately leading to serious damage to the learning and memory ability of rats.^[27]^ It can also reduce the number of hippocampal neurons and damage long-term memory.^[28]^ Ischemia and hypoxia can inhibit the expression of BDNF and glialcellline-derivedneurotrophic factor, leading to hippocampal atrophy,^[29]^ neurological dysfunction, and learning and memory impairment in rats.^[30]^ Hypercapnia combined with hypoxemia can improve the nuclear translocation efficiency of HIF-1α in hippocampal neurons, promote the expression of matrix metalloproteinases, damage the blood-brain barrier in the hippocampus, and lead to cognitive dysfunction.^[31]^ Hypoxic preconditioning downregulated the expression of miR-103, reduced the incubation period, increased the number of crossings, and improved hypoxic tolerance and cognitive function in mice.^[32]^

3.2. Neurons and blood vessels

Hypoxia at high altitudes led to the widening of the gap around nerve cells, swelling of cells, atrophy and deformation of neurons, disordered arrangement, and loss of neurons in the hippocampal CA1 region of rats.^[33]^ Hypoxia reduces the proliferation and differentiation of hippocampal dentate gyrus neurons in mice, which may be related to the ERK signaling pathway.^[34]^ Repeated hypoxic exposure reduced the metabolic rate and promoted the expression of immediate early gene products in hippocampal neurons.^[35]^ Hypoxia increases the expression of neurodegenerative genes in hippocampal neurons.^[36]^ Hypoxia increases the number of proximal dendrites of hippocampal CA1 pyramidal neurons and prolongs the branches of apical dendrites, affecting certain functions of hippocampal neuronal circuits.^[37]^ Hypoxic exposure promotes the growth of hippocampal neuronal axons and enhances the reverse transport function of mitochondrial axons, which may be achieved by promoting the expression of the mitochondrial transport regulatory protein HUMMR.^[38]^ The decrease in calcium accumulation in hippocampal CA1 neurons during hypoxia may be related to the enhanced hypoxia tolerance in hippocampal neurons caused by long-term hypoxia.^[39]^ Hypoxia improves the permeability of the blood-brain barrier through the ERK signaling pathway.^[40]^ After the administration of kaempferol, the learning and spatial memory abilities of rats were restored, and neuronal degeneration was reduced.^[41]^ Egg-laying defective nine 1 regulates the hypoxic response of hippocampal neurons by regulating the transcriptional activity of HIF-1α. Therefore, inhibiting expression of Egg-laying defective nine 1 has a protective effect on hippocampal neurons.^[42]^ Hypoxia combined with propofol can induce iron death, mitochondrial swelling, cristae dissolution, and disappearance in hippocampal neurons by promoting the expression of the transferrin receptor and ferrous ions, further aggravating the damage of immature hippocampal neurons.^[43]^ Astragalus membranaceus protected hippocampal neurons from intermittent hypoxia-induced injury in rats.^[44]^ The expression of synaptophysin in the hippocampus decreased, and the expression of vascular endothelial growth factor increased in the hypoxia group.^[45]^ Hypoxia disrupts the formation of hippocampal capillaries. The older the age, the lower the plasticity of hippocampal capillaries.^[46]^

Acute high-altitude hypoxia can promote the necrosis of pyramidal neurons in the hippocampal CA1 area, mitochondrial swelling, and the appearance of a large number of mitochondrial autophagosomes, leading to the apoptosis of hippocampal neurons. This mechanism may be regulated by the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mTOR signaling pathway.^[47]^ After the AAV-syn-BDNF-Enhanced green fluorescent protein virus was transferred into hippocampal neurons and treated with acute hypobaric hypoxia, the spontaneous bioelectrical activity of the neurons was restored, the anti-hypoxia ability was improved, and neuropathy was reduced.^[48]^ Acute high-altitude hypoxia reduces cerebral blood flow and damages the central nervous system of mice.^[49]^

Chronic hypobaric hypoxia exposure leads to increased neuronal degeneration in the hippocampal CA3 region, which is related to the regulation of tropomyosin receptor kinase B. Hypoxia-induced memory impairment leads to decreased spatial memory in adult rats by reducing the immunoreactivity of the postsynaptic density protein kalirin-7.^[50]^ Intermittent hypoxia can promote hippocampal functions, including cell proliferation, migration of newborn neurons, and increased spinous processes, which may be related to notch1-mediated neurogenesis.^[51]^ Intermittent hypoxia inhibits the development of adult hippocampal neurons, impairs the spatial memory ability of animals, and increases the generation of adult neurons after the termination of hypoxia. HIF-1α in intermittent hypoxia-dependent hippocampal neurons is activated in early neurons and promotes the formation of adult neurons after removing hypoxia conditions.^[52]^ Intermittent hypoxia leads to decreased growth of growth hormone and vascular endothelial growth factor (VEGF) in the hippocampus, resulting in neuronal loss and cognitive impairment.^[53]^ Chronic intermittent hypoxia reduces synaptic plasticity by inhibiting the protein kinase A signaling pathway, leading to neuronal damage.^[54]^ Intermittent hypoxia promotes neuronal deformation, nuclear membrane blurring, and mitochondrial vacuolation in the rat hippocampal CA1 region. Edaravone increases and reduces the expression of apoptotic proteins and autophagy in hippocampal neurons and plays a neuroprotective role.^[55]^

Hypoxic ischemia promotes the expression of hypoxia-inducible factor-1, HIF-1α, which leads to decreased systolic and diastolic blood pressure and mean arterial pressure in rats. After treatment with salidroside, hemodynamic indices improved. This result is consistent with the regulation of HIF-1α protein.^[56]^ Ischemic hypoxia can affect the survival rate of hippocampal neurons and promote neuronal degeneration by promoting the expression of HIF-1α.^[57]^ The expression of HIF-1α positive cells increased in the hippocampus of rats in the hypoxia group, and the density of VEGF-positive cells was higher than that of the control group.^[58]^ Studies have found that early inhibition of the Toll-like receptor 4 (TLR4) signaling pathway can increase the density of the spinal cord in the hippocampus, improve the loss of neurons, and decrease synaptic plasticity caused by hypoxic-ischemic injury.^[59]^ Ischemia and hypoxia reduce cerebral perfusion, affect brain metabolism, and damage hippocampal neurons in oligodendrocyte nuclei.^[60]^ Prenatal hypoxia reduced reelin expression in the rat hippocampus but did not affect VEGF expression.^[61]^ Hypoxia induced by hypercapnia reduces the expression of proteins involved in neuronal stratification and migration in the hippocampal CA1 region, particularly in the hippocampal pyramidal cell layer.^[62]^ Hypoxia and hypoglycemia can reduce the synaptic plasticity of hippocampal neurons, resulting in reduced cAMP-response element binding protein (CREB) and BDNF expression. After using jitianjiannao, the CREB/BDNF pathway is activated, which enhances the expression of synaptic plasticity proteins, promotes synaptic remodeling, and has a protective effect on hippocampal neurons in rats.^[63]^ The administration of sodium pyruvate under hypoxic conditions can activate autophagy signaling and reduce apoptosis in hippocampal neurons, thus playing a neuroprotective role and reducing hypoxic injury.^[64]^ Hypoxic preconditioning can improve cell viability and protect hippocampal neurons from hypoxia-induced injury.^[65]^ Intermittent preconditioning for 6 h per day can effectively improve the number of remaining hippocampal neurons and tissue ultrastructure, which is related to the regulation of signaling pathways, including the endocytosis signaling pathway, longevity regulation pathway, and RNA transport.^[66]^

3.3. Synaptic morphology, function, and plasticity

Hypoxia exposure inhibits the expression of developmental proteins in hippocampal neurons, including the hypoxia-related molecules fibronectin 1 and filament protein C, ultimately leading to neuronal damage.^[67]^ The expression of synaptic plasticity proteins in hippocampal CA1 neurons was significantly decreased, the number of synapses in the neurons was reduced, and the synaptic gap was unclear. With the extension of intermittent hypoxia time, synaptic damage becomes more serious.^[68]^ Hypoxia leads to an abnormal increase in glutamate levels, shortening of neurites, imbalance in internal homeostasis, and memory impairment.^[69]^ The level of extracellular γ-aminobutyric acid (GABA) in hippocampal synaptosomes of rats exposed to hypoxia increased.^[70]^

High-altitude hypoxia exposure can reduce the myelin sheath content and decrease the thickness of the myelin sheath in the corpus callosum and DG area of the hippocampus in adult mice. Reoxygenation can return to normal within 2 months, and hypoxic reoxygenation does not affect axon content.^[71]^ High-altitude hypoxia induces a decrease in the density of dendritic spines in hippocampal CA1 neurons in mice. After using inhibitors, the morphological changes in dendritic spines in hippocampal CA1 neurons were protected, and damaged learning and memory abilities were restored.^[72]^ Butylphthalide pretreatment can increase acetylcholine and acetylcholine activity and reduce the damage caused by acute hypobaric hypoxia on memory function in mice.^[73]^ Inhibition of adenosine by hypoxia can lead to neuronal damage, behavioral changes in the hippocampal CA1 area, and impaired memory.^[74]^

Chronic hypoxia affects myelination and motor coordination in adult mice.^[75]^ Hypoxia for 30 min reduced excitatory postsynaptic potential and synaptic transmission of evoked fields in the hippocampal CA1 region.^[76]^ Reversible synaptic inhibition caused by hypoxia for 40 minutes was transformed into the irreversible disappearance of the synaptic potential through an NMDAR-dependent mechanism. This phenomenon occurs in the presence of plasma 1, and the presence of a transport inhibitor cannot block the effect mediated by plasma 1, leading to the accumulation of unknown transporters, cell swelling, and further damage to hippocampal neurons.^[77]^ Short-term hypoxia can damage GABAergic neurons and reduce their inhibitory effects, which may be achieved through the PI3K signaling pathway.^[78]^ Continuous hypoxia affects synaptic dendritic spine density in the hippocampal CA1 region of senescence accelerated mouse male mice and reduces synaptic plasticity. After treatment with dihydrotestosterone, the expression of the synaptic plasticity proteins in the hippocampus of mice increased.^[79]^ Studies have found that ligustrazine hydrochloride has a protective effect on the learning and memory abilities of the brain under hypobaric hypoxia, and its mechanism may be related to an increase in the expression of forkhead box p2 in the hippocampus of rats.^[80]^

Chronic hypobaric hypoxia exposure inhibited the expression level of fillin in the hippocampal CA1 region of mice. It resulted in morphological changes in dendritic spines in the hippocampal CA1 region, including an increase in the length of dendritic spines and apical dendritic spines.^[81]^ Chronic high-altitude hypoxia can damage the hippocampal neurons, promote apoptosis, affect oxidative stress, and free radical levels, and lead to cognitive dysfunction. One of these mechanisms involves increased glutamate and receptor-mediated excitotoxicity.^[82]^

Chronic intermittent hypoxia can damage cholinergic neurons in the basal forebrain through endoplasmic reticulum stress, oxidative stress, and inflammatory reactions and cause cognitive dysfunction in mice. The basal forebrain cholinergic system can play a role in endoplasmic reticulum stress, oxidative stress, and inflammatory reactions reduce damage to cholinergic neurons, and thus restore cognitive function in mice.^[83]^ Severe chronic intermittent hypoxia results in an increase in the number of GABA neurons in the hippocampus of mice, and the number of GABA neurons in males was higher than that in females.^[84]^ Chronic intermittent hypoxia inhibits the mTOR/NF-κB signaling pathway, leading to decreased BDNF-mediated synaptic plasticity and cognitive impairment.^[85]^ After intermittent hypoxia and continuous hypoxia, the activity of carbachol in the DG region of the rat hippocampus decreases, which may be due to hypoxia inhibiting the activity of the G protein in the DG region and affecting the function of the hippocampus.^[86]^

Ischemic hypoxia leads to neurodegeneration by damaging the CA1 synaptic transmission and cell integrity.^[87]^ Ischemic hypoxia inhibits the expression of glutamate and aspartic acid in the CA1 region of the hippocampus, leading to an increase in the number of damaged neurons.^[88]^ Hypoxic ischemia inhibits the synaptic plasticity of hippocampal neurons, inhibits Pro BDNF to BDNF transformation, and leads to brain injury by downregulating the BDNF/TrkB pathway.^[89]^ Convulsions induced by ischemia and hypoxia change the purinergic and neuroinflammatory components in an age-dependent manner in the developing mouse hippocampus.^[90]^ Perinatal hypoxia affects synaptic plasticity and cognitive function and leads to long-term biological dysplasia.^[91]^ Perinatal ischemia and hypoxia can reduce the expression of hippocampal interneurons, such as somatostatin and neuropeptide Y, and affect brain development^[92]^ and the release of GABA in the nerve endings of the hippocampal tissue and damage to the hippocampus.^[28]^ Repeated hypercapnia and hypoxia increase the expression of the acetylcholine receptor subunit in the hippocampus, but the increase in the CA1 area was not obvious.^[93]^

3.4. Immunity and inflammation

High altitude and low-pressure hypoxia can increase the expression of adenosine A2A receptor and tumor necrosis factor-α (TNF-α) in rat hippocampal brain, leading to the accumulation of microglia, mediating the occurrence of neuroinflammation, and leading to acute spatial memory impairment in mice.^[94]^ Hypobaric hypoxia causes significant damage to the hippocampal CA1 region. Hypoxia activates astrocytes and microglia, increases pro-inflammatory factor levels, and induces neurodegeneration.^[95]^ With the increase of hypoxia altitude and time, the PI3K/Akt/mTOR-HIF-1α signal pathway was gradually inhibited. Verbascoside can alleviate damage to hippocampal tissue and oxidative stress in vivo and has a certain protective effect on the cognitive function damage caused by hypoxia at high altitudes.^[96]^ Hypoxic exposure can promote the expression of inflammatory factor TNFα in the hippocampus of mice and inhibit the expression of neuroprotective genes such as BDNF and CREB in the hippocampus; however, Genistein can reverse the situation.^[97]^ Hypoxia induces an inflammatory reaction in HT22 cells. After treatment with dexmedetomidine, the level of MMP relatively increased. TNF-α expression level was relatively low, which inhibits the occurrence of inflammatory reaction.^[98]^ After moderate hypoxia, the number of immunopositive neurons in the dorsal hippocampus and abdomen increased, which may have been caused by the activation of intermediate neurons containing neuropeptide Y.^[99]^

Acute hypoxia can promote the activation of microglial type M1 and reduce the activation of microglial type M2, accompanied by an increase in related pro-inflammatory cytokines and chemokines and a decrease in anti-inflammatory cytokines.^[100]^ Acute hypobaric hypoxia exposure promotes hippocampal TLR-4, and Tongxinluo intervention can inhibit TLR4/Myeloid differentiation primary response protein 88/NF-κB. Activating the B signaling pathway can reduce the expression of the above inflammatory factors, reduce the inflammatory reaction in the hippocampus, and improve brain edema.^[101]^

Chronic intermittent hypoxia induces inflammation both in vivo and in vitro in mice, leading to inflammatory responses and neuronal apoptosis in the hippocampus. The SUMO-specific protease reverse inflammatory responses.^[102]^ Chronic intermittent hypoxia promotes the activation of microglia and expression of pro-inflammatory factors in the rat hippocampus, impairs the learning and memory abilities of rats, and affects cognitive function.^[103]^ Chronic intermittent hypoxia via NF-κB-mediated c-Jun N-terminal kinase signaling pathway promotes the expression of inflammatory factors in the hippocampus, which leads to severe oxidative stress in the hippocampus and impairs cognitive function.^[104]^ Chronic intermittent hypoxia promotes the production of hippocampal TNFα and interleukin-1 β. Propofol significantly improved cognitive function in mice, possibly related to its inhibition of hippocampal inflammatory response.^[105]^ Chronic intermittent hypoxia promotes the expression of inflammatory factors in the hippocampus, induces an oxidative stress response, and leads to depression-like behavior in rats.^[106]^ Intermittent hypoxia promoted malat1 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) expression in hippocampal neurons, which was negatively correlated with the expression of mir-224-5p. MALAT1 can affect the expression of NLRP3 by regulating mir-224-5p, while up-regulating mir-224-5p can reduce the inflammatory activation of microglia and ultimately regulate NLRP3/IL-1 in the hippocampus.^[107]^ IH-induced cognitive impairment is closely related to oxidative stress injury in hippocampal neurons. Compared with the CA3 region, CA1 region is more vulnerable to oxidative stress. Edaravone can reduce hippocampal damage by clearing excess ROS to normalize the oxidative balance.^[108]^ Intermittent hypoxia induces inflammatory factors P2X7 receptor(P2X7R) and TNFα in the rat hippocampus; when the concentration of P2X7R is increased and the expression of P2X7R is inhibited, the transformation from M1 to M2 type microglia is inhibited, and the expression level of pro-inflammatory factors in the hippocampus is decreased.^[109]^ Intermittent hypoxia promotes the expression of neuroinflammatory factors and inflammatory changes in microglia of the dorsal hippocampus by affecting cognitive function in mice.^[110]^ Intermittent hypoxia promotes Peroxisome proliferator-activated receptor γ post-translational modification and can cause inflammation and neuronal apoptosis, leading to cognitive impairment.^[111]^ Intermittent hypoxia leads to oxidative stress injury and cognitive impairment in mice; Peroxisome proliferator-activated receptor γ pioglitazone, an agonist, can improve oxidative stress injury and cognitive impairment caused by intermittent hypoxia.^[112]^

Hypercapnia can promote the activation of the NLRP3 inflammasome in microglia activated by hypoxia and pro-il-1 (Cut to IL-1), which can then induce the inflammatory reaction of the central nervous system, leading to the apoptosis of hippocampal neurons and aggravating the damage to cognitive function.^[113]^ After hypoxic preconditioning, the expression of NF-kB and phosphorylated CREB increases in the dentate gyrus of rats, increasing immune reactivity and brain tolerance to hypoxia.^[114]^ After hypoxia and reoxygenation, the expression of inflammatory genes in the hippocampus increases.^[115]^

3.5. Oxidative stress, apoptosis, and autophagy

Hypoxia for 6h in HT22 mouse hippocampal cells promoted PGRN expression, leading to brain injury.^[116]^ Hypoxia-induced oxidative stress in the hippocampus promotes memory and cognitive impairments, leading to neurodegeneration.^[117]^ Hypoxia increases lactate dehydrogenase (LDH) and intracellular calcium overload, reduces total superoxide dismutase activity, increases malondialdehyde levels, and promotes oxidative stress and apoptosis.^[118]^ The antioxidant system in the brain was damaged, and the cells were apoptotic when rats were exposed to 7% oxygen for 6 hours. Compared to the cortex, apoptosis of hippocampal neurons is more obvious.^[119]^ Hypoxia for 18 hours promotes the expression of HIF-1α, leading to loss of mitochondrial membrane potential, nerve cell rupture, and apoptosis.^[120]^ Hypoxia inhibits BDNF expression and reduces the anti-apoptotic ability of hippocampal neurons.^[121]^ The learning and memory abilities of rats are impaired in natural high-altitude hypoxic environments. As mitochondrial damage in hippocampal neurons increases, neuronal apoptosis increases and nerve regeneration decreases.^[122]^ Hypoxia can also increase the unfolded protein response, promote apoptotic signal transduction, and increase tau phosphorylation, leading to cell dysfunction.^[123]^ After treatment with melatonin, malondialdehyde expression and apoptosis in the hippocampus decreased.^[122]^ Hypoxia promotes the combination of HIF-1α and hypoxia response elements, impairs the hypoxia tolerance of NMR hippocampal neurons, and induces apoptosis of hippocampal neurons. Studies have found that after 8 h of hypoxia, the protein in hippocampal neurons increased, which may be caused by the increased expression of HIF-1α, further reducing the apoptosis of neurons caused by hypoxia.^[123]^ Hypoxia enhances the migration of neural stem cells, causes cell death, and contributes to the survival of newborn cells in the hippocampus.^[124]^ The damage caused by hypoxia to hippocampal neurogenesis and cell death can be reversed by melatonin, which may be through inhibition of the activation of hippocampal NF-κB.^[125]^ The autophagic activity of the hippocampal neurons was relatively low. When rats are exposed to hypoxia, the protein level of autophagy markers in the hippocampus is low, which indicates the vulnerability of hippocampal CA1 neurons to some extent. In the hippocampus, the exposure to hypoxia resulted in a decreased autophagy marker, which was followed by activation of the autophagy-related gene expressions.^[126]^

Hypobaric hypoxia exposure promotes the expression of apoptotic proteins in the hippocampus, which may be related to the increased expression of c-Jun N-terminal kinase, and the depletion of keratin 18 may be a possible mechanism.^[127]^ Hypobaric hypoxia promotes the leakage of LDH and the expression of apoptotic proteins, leading to oxidative stress, excitotoxicity of glutamate, and neurodegeneration.^[128]^

Chronic intermittent hypoxia promotes the apoptosis of hippocampal neurons and affects the spatial learning and memory abilities of rats.^[129]^ Intermittent hypoxia promotes the expression of superoxide dismutase in hippocampal neurons, leads to oxidative stress and apoptosis, causes spatial reference and working memory disorders in rats, and leads to cognitive impairment.^[130]^ Intermittent hypoxia increases the expression of apoptotic proteins in the hippocampus and prolongs the escape latency in rats, suggesting that their learning and spatial memory abilities are impaired.^[131]^ Intermittent hypoxia promotes autophagy in hippocampal neurons, resulting in chromatin concentration, cell fragmentation, and a reduced quantity of hippocampal neurons.^[132]^

After 6 hours of sublethal hypoxia, the synthesis of nitric oxide synthase increased, leading to cell necrosis in the hippocampus and cortex.^[133]^ Ischemia and hypoxia lead to developmental disorders of hippocampal neurons, characterized by hippocampal atrophy, decreased neuronal count, and increased cell apoptosis. Hypoxia ischemia injury leads to increased expression of key molecules regulating apoptosis in the hippocampal CA1 region, resulting in apoptosis of hippocampal astrocytes and further leading to neuronal degeneration.^[134]^ After moderate focal ischemia and hypoxia, many hippocampal neurons were damaged and atrophied. Light microscopy shows that dead neurons are similar to apoptotic neurons.^[135]^ Hydrogen sulfide protects rat hippocampal neurons from hypoxia-reoxygenation (H/R) injury by promoting RhoA phosphorylation of ser188 and reducing the leakage of LDH and neuron-specific enolase (NSE). After hypoxic reoxygenation, cell viability is damaged, resulting in the leakage of LDH and NSE.^[136]^ Sodium cyanide induces chemical ischemia and hypoxia in hippocampal neurons by promoting the production of prostaglandin G/H synthase 2, resulting in increased hippocampal neuronal nuclear fragmentation and decreased cell viability. Hydroxygentine exerts neuroprotective effects by inhibiting the production of prostaglandin G/H synthase 2.^[137]^ Hypoxic preconditioning can improve hypoxia tolerance, maintain the stability of hippocampal formation, and protect the hippocampus from hypoxic damage by activating endogenous antioxidant defense systems.^[138]^ Hypoxic reoxygenation for 6 h induces oxidative stress in cells, leading to apoptosis, which is related to a decrease in miR-200 family expression.^[139]^ Hypoxic reoxygenation can also damage the mitochondrial membrane potential in the hippocampus, resulting in increased ROS production and decreased antioxidant capacity.^[140]^

3.6. Mitochondria and metabolism

Hypoxia reduces the rate of mitochondrial oxygen consumption induced by ADP in the mouse hippocampus, whereas a ketogenic diet increases the rate of oxygen consumption and the expression of mitochondrial division and fusion proteins in the mouse hippocampus.^[141]^ Under mild hypoxia, neurons may reduce apoptosis of hippocampal neurons by upregulating lactate dehydrogenase A expression.^[142]^ Hypoxia causes mitochondrial dysfunction, increased excitotoxicity, and neurodegeneration in rat hippocampal neurons, which may be related to the regulation of mitochondrial biogenesis by ERK-nuclearfactor erythroidderived 2-like 2.^[143]^ Hypoxia combined with hypercapnia promotes the expression of proteins related to the permeability regulation of blood-brain barrier in the hippocampus, leading to the destruction of blood-brain barrier in SD rats.^[144]^ Rhodiola rosea can resist hypoxic injury by inhibiting the opening of the mitochondrial membrane transport pore, preventing changes in mitochondrial membrane potential and the difference in Ca^2+^ concentration inside and outside the mitochondrial membrane, increasing the expression of Bcl-2, reducing the expression of Caspase3, and inhibiting neuronal apoptosis.^[145]^ In addition, hypoxia can lead to reduced expression of glycolytic genes, such as glycerate kinase 1, in the hippocampal tissue, and its expression decreases with age.^[2]^ Hypoxia leads to lipid peroxidation and DNA damage in the hippocampal neurons, and the molecular chaperone heat shock protein 90 is involved in this pathological process.^[146]^ Severe hypoxia can promote hippocampal DNA fragmentation and reduce thiobarbituric acid-reactive substances, whereas hypoxic postconditioning can inhibit these phenomena and protect hippocampal neurons.^[147]^ Under severe hypobaric hypoxia, the expression of glucose-6-phosphate dehydrogenase and the levels of NADPH and total glutathione in the rat hippocampus decreased. After post-treatment, the activity of glucose-6-phosphate dehydrogenase was restored, and the levels of NADPH and total glutathione increased slowly, reducing neuronal death of neurons.^[148]^ Curcumin intervention can improve the decrease in dendritic spine density, synaptic damage, and learning and memory impairment of hippocampal neurons induced by hypoxia by regulating phenylalanine metabolism, glucose metabolism, and bile acid synthesis in the hippocampus of hypoxia-exposed mice.^[149]^

Acute hypobaric hypoxia leads to an increase in lipid peroxide content and free radicals in hippocampal neurons.^[150]^ Acute high altitude hypoxia affects the level of energy metabolism in rats, which shows that the mitochondrial membrane potential of hippocampal neurons, mitochondrial respiratory chain complexes Ⅰ, Ⅲ and Ⅳ and ATPase activity are significantly decreased. After well point bloodletting, the above situation was improved, which may be related to the reduction of mitochondrial autophagy level mediated by PI3K-Akt-mTOR signaling pathway.^[151]^

Chronic hypoxia leads to the formation of immature dendritic cells by altering energy metabolism and neurotransmitter transmission in the hippocampus, which affects fear memory in the hippocampus.^[152]^ Chronic hypobaric hypoxia exposure promotes the expression of aging proteins in the hippocampus, inhibits tau expression, and leads to a decline in learning and memory abilities in rats. Changes in the protein metabolism of the hippocampal mitochondrial morphology lead to lipofuscin accumulation, which further causes the degeneration of hippocampal CA3 neurons.^[153]^

Chronic intermittent hypoxia can lead to the damage of hippocampal neurons in rats, resulting in the serum HIF-1α. NSE concentration increased; however, with the extension of hypoxia time, serum HIF-1α expression increased after the intervention of Dazhu Hongjingtian, and the damage of hippocampal neurons was improved.^[154]^ Chronic intermittent hypoxia results in a decrease in body weight and hippocampal weight in rats and metabolic changes in the hippocampal tissue, including a decrease in glutamate levels.^[155]^ Studies have found that chronic intermittent hypobaric hypoxia can alleviate the decline in mitochondrial membrane potential and outflow of the mitochondrial apoptosis promoter protein cytochrome c during cerebral ischemia.^[156]^ Huperzine A alleviates chronic intermittent hypoxia-induced hippocampal neuronal apoptosis, oxidative stress, and synaptic plasticity damage by reducing iron deposition in mouse brains.^[157]^ Intermittent hypoxia promotes the generation of oxygen free radicals, reduces the number of mitochondria, and affects the morphology and structure of the hippocampus in rats.^[158]^ Intermittent hypoxia leads to the damage of multiple cognitive domains in the hippocampus, and the level of substance metabolism in the hippocampus increases, suggesting that the damage of cognitive domains may be related to the loss of hippocampal function.^[159]^ Intermittent hypoxia affects the level of oxidative bases in hippocampal mitochondrial DNA (mtDNA) and the expression of key enzymes for mitochondrial base excision repair at the gene level and significantly reduces the contents of total mtDNA1 and mtDNA3.^[160]^

Hypoxic preconditioning changes the metabolic patterns in the serum and hippocampus of mice, and the metabolism of glutathione, alanine, aspartate, and glutamate in the hippocampus changes significantly.^[161]^ Hypoxia preconditioning enhances the expression of Thioredoxin-2 in hippocampal mitochondria, which may be a reactive regulator of hypoxia.^[162]^ Hypoxic preconditioning exerts neuroprotective effects by affecting energy metabolism in hippocampal cells through the mTOR/autophagy signaling pathway.^[163]^ The main source of NADPH in the brain is the pentose phosphate pathway, which is involved in glucose metabolism. Studies have found that Timely supplementation with NADPH after ischemia or hypoxia can improve oxidative stress, apoptosis, and neuronal loss in the hippocampus.^[164]^ Hypoxic reoxygenation promotes the expression of apoptosis-inducing factor, mitochondrial division-related proteins and Rho a protein 1 and damages hippocampal neurons.^[165]^ Hypoxia treatment can promote lipopolysaccharide to increase the level of chemokine ligand 10 in the serum and hippocampus of mice, and its mechanism is related to NF-kB signaling pathway activation.^[166]^

4. Conclusions

Changes in oxygen concentration affect the hippocampal morphology and structure. Morphological and functional changes in the hippocampus are affected by hypoxia type, hypoxia time, and oxygen concentration. Hypoxia affects hippocampal learning and memory ability, oxidative stress level, neuron development, and metabolism (Fig. 2). Further intervention and the discovery of therapeutic targets will help stabilize hippocampal function under hypoxia. It is expected that in the future, there will be more means to treat the consequences of abnormal changes in the hippocampus under hypoxic environments and develop an effective defense.

Acknowledgments

These figures were created with BioRender.com.

Author contributions

Conceptualization: Ge Rili.

**Funding ** Ma Shuang, Ge Rili.

Investigation: Ma Shuang.

Methodology: Ma Shuang.

Validation: Ge Rili.

**Writing – original ** Guan Lu.

**Writing – review & ** Guan Lu.