Lecture 5 - Viruses in Neurogenesis + Aging

neurodevelopmental hypothesis

neuropsychiatric conditions like SCZ are the result of viral infections or other types of agents to cause neuropathological processes during NS development, from late trimester to adolescence and early adulthood when processes like cortical myelination might be affected its a very vulnerable time for your brain, the insults may lead to pathological brain circuit function that results in mental disorder symptoms like delusions or mood disturbances being the modern idea of neuropsychiatry and neurosurgery, you get exposed to viruses all the time just depends on immune system and viral exposure

what are the mechanisms of viral impact on the brain?

direct infection of neurons or glial cells that are often killing them once infected through apoptosis or necrosis (caspase 3), induction of neuroinflammation, latent viral infections and reactivation especially under stress and more suppressed immune system playing a role in neurodegenerative disease like AD or MS by affecting oligodendrocyte myelination,

latent viral infections

when you get an infection and recover but the virus never really goes away and can potentially reactivate

how do viruses shape the brain?

they do so indirectly and directly by influencing neural development, microglia activation, synaptic pruning, circuit refinement so how neurons connect with each other or killing cells, long term cognitive effects often arise from altered circuitry rather than neuron loss which might result in memory changes + disorders like SCZ, so basically virus exposure will cause immune signallling which activates microglia to cause synaptic pruning to form circuit structure which in turn forms behaviour, brian development of brain and learning relie on shared biological machinery

what are viruses?

non-living nucleic acid containing infectious aging, they are neurotropic so they are attracted to the nervous system and to cells derived from the neuroectoderm but also microglial cells, capsid and nucleic acids are key structures

neuroectoderm

makes astrocytes, oligodendrocytes, neurons, etc

capsid

viral identifier, it envelops the nucleic acid + important in AIRE

what is the general route of viral infection?

it can either infect via the olfactory or gastric system, this causes pro-inflammatory cytokines to activate which disrupts the BBB disruption by breaking down claudin-5, occludin and ZO-1 which are tight junction proteins, the virus needs to break the BBB to cause infections, then once the cytokines enter they activate microglia which surrounds the neurons and attacks it or releases more pro-inflammatory cytokines

trigeminal nerve

this is what gets infected once the virus enters the brain, its also known as cranial nerve 5

why is the developing brain vulnerable?

it has high amount of neural progenitor proliferation which we don’t want to disrupt, it activates neuronal migration and synaptogenesis, the BBB is immature so it allows cells and molecules to enter, developmentally programmed microglia learn by adapting to what they are programmed to do in early development so they have less experience when still developing cause what it recognizes in development leads to immunologic history and the more the better

microglia

act as immune cells and circuit sculptors in the developing brain, viruses influence them through interferon signaling, complement pathway activation and result in altered pruning thresholds which isn’t good cause normally inactive synapses get pruned away but altering threshold makes them more or less active so affects synapse numbers which is bad

where do microglia come from?

they arise from yolk-sac macrophages very early in embryogenesis (E7-E9 in mice) before neurons and astrocytes, they enter the brain while circuits are still forming and receive developmental cues via CSF-1, IL-34, TGF-B and neuronal activity signals, these cues program their identity, gene expression and future behavior, so the main thing is they aren’t later invaders reacting to the brain but rather developmental residents part of normal brain development

microglia stages

in the embryonic/early postnatal stage they guide neuronal survival, sculpt axonal tracts and remove excess progenitors, in early development of circuits and critical periods they mediate synaptic pruning via complement C1q/C3-CR3 and tune excitation inhibition balance, in adolescence they refine long range connectivity, shape learning-relevant circuits at synapse level and in adulthood they maintain synapses, monitor homeostasis rather than remodel just to ensure that synapses are working properly

what happens if the mitochondria program is interrupted?

if there is some kind of infection, stress or viral exposure the incorrect microglial developmental program may be activated, circuit refinement may be altered permanently so it might never turn on or be turned on all the time, this links microglia to neurodevelopmental disorders like ASD and schizophrenia,

developmentally programmed microglia

microglial cells whose identity, gene expression and functions are pre-specified by developmental timing to actively shape brain circuits, rather than merely responding to injury or disease

microglia synaptic pruning mechanisms

weak synapses are tagged by C1q and C3, microglial CR3 mediates the elimination of cells and components or cells so the inactive synapses known as activity dependent refinement, the synapses that are inactive get targeted for removal by phagocytosis

activity-regulated cytoskeletal (Arc) gene

it encodes a protein that are critical for memory consolidation, it is one of the most tightly regulated molecules known as neuronal activity controls Arc mRNA induction, trafficking and accumulation, Arc protein production, localization and stability, certain forms where the gene is overactive can cause epilepsy

how does Arc work?

Arc is expressed in cells within 5 minutes so very quickly in response to synaptic activity or external stimuli, the Arc mRNA travels within an hour to the most distant tips of dendrites, the branched extensions of neurons where it accumulates and undergoes translation, lots of different things can stimulate it

how do we get rid of Arc ?

through the ubiquitination pathway that degrades it via a proteosome, we need a way to get rid of it cause if it lasts too long we would remember everything which isn’t good

what is the point of having Arc?

it is originally described for learning and memory, it might have actually been derived from a viral capsid containing your own mRNA then released as an exosome to nearby neurons that could also take it up

what is Arc made of?

the genetic sequence of it resembles that of retroviral gene Gag, and that it originated from the Ty3/Gypsy retrotransposon family which is an ancestor that became integrated into higher vertebrates, the crystal structure of its subunits are similar to the capsid region of the HIV gag protein which is also a human retrotransposon type virus, the retroviral gag protein binds to its own mRNA then gets encapsulated into capsids, the Arc mRNA levels in the purified Arc capsids were compared to those of highly abundant bacterial RNA, looking at some kind o fvirus once they were assembled together, the Arc mRNA levels were 10 fold higher than the bacterial RNA in the capsids and Arc capsisds are not very specific for any particular RNA, they act as exosomes

how do arc capsids act as exosomes?

on different types of packages that contain the capsids, they could be taken up + internalized by nearby neurons and release Arc mRNA inside those neurons

Poly I:C model for maternal immune activation

produces altered excitation-inhibitory balance in the PFC, excessive synaptic pruning and behavioral phenotypes without viral particles by mimicking viral dsRNA that activates immune signaling pathways, especially TLR3, in the placenta it triggers immune activation and cytokine release altering fetal brain development indirectly

how does the poly I:C model work?

it increases C1q/C3 tagging, excessive synapse elimination and altered cortical + HPC circuits affecting learning and memory, first they inject poly I:C into the rat that has never given birth before then at gestational day 19 it starts to experience weight loss, sickness behavior and serum cytokine elevations changing, then they induce pregnancy and find that the poly IC mice have decreasesd litter size so not all fetuses make it to term, the mother has lower body weight than males at baseline, serum cytokine levels are unchanged in adult poly I:C offspring

TLR3 in poly I:C model

it affects developing embryos at gestational day 19 so they are almost ready to be born like 2 days away

HSV-1

herpes simplex virus 1, causes infection latently altering axonal transport and synapse stability

HIV proteins

includes Tat and gp120, it disrupts NMDA receptor signaling which alters learning and memory

viruses and synaptic plasticity

alterations in synaptic function is the result of virally induced immune activation, HPC and prefrontal circuits rely on precise pruning cause the brain is the most time dependent structure so this is very important, viral inflammation alters LTP/LTD balance and these are involved in learning and memory, especially in early development but also in the adult brain, memory precision and flexibility are reduced

west nile virus

caused by mosquitos, survivors show long term memory impairment, reduced adult hippocampal neurogenesis, persistent microglial activation suggesting its a long term memory process so recovery is gonna be very hard

HSV1 and HSV2

they are two highly contagious viruses that can cause outbreaks of water blisters on the skin and mucous membranes of the mouth, lips, nose, genitals and eyes, these viruses along with VSV(varicella zoster virus) are never cleared from the body after infection but instead they embed themselves in nerve cells cause the virus is neurotropic where the viruses remain in a latent/dormant state so it can spontaneously reactivate

HSV-1 in the CNS

it primarily enters through the olfactory route, some viruses cross the BBB like HSV and zika directly, they interact with neural cells, potentially affecting brain function and development, olfactory entry is retrograde so it goes back towards the brain where as oral entry is anterograde, the virus can also enter due to HSV-1 reactivation into the brain via the trigeminal ganglion, the virus lives in those cells via synaptic connections going into the CNS

HSV-1 CNS infection through the hematogenous route

the mother with the active virus allows travel through the umbilical vein through the lymphatic system, this then affects the baby through placental transmission, this affects neurons in the lateral ventricle and HPC which are areas where there are lots of neural progenitor cells in infants, this results in reduced proliferation, maturation and differentiation of neural stem cells, this

how do viruses cause microencephaly?

by disrupting neurogenesis, they may alter neural stem cell proliferation and differentiation while also producing neuronal stem cell death by activating apoptotic programs which we dont want in the developing brain

Zika virus neurodevelopment

infects radial glial and neural progenitors, it disrupts cell-cycle control and centrosome function in these cells ultimately leading to both reduced neuron number and altered cortical layering

cytomegalovirus (CMV)

might leads to massive cognitive defects and altered circuit formation, it alters white matter maturation, it disrupts interneuron development in the brain as it alters circuits that require inhibitory interneuron control so too much excitation happening, it produces long term cognitive effects without massive neuron loss, viral latency

links to AD

most common type of dementia, it occurs after 60 years of age, in young ppl 13% of cases show an autosomal dominant pattern of inheritance, an increased amount of beta amyloid is found in the brains of AD patients, the overproduction may be related to the mutation of the genes encoding PSEN1 and PSEN1 (presenilins) which help cleave amyloid precursor protein (APP), if they are overactive it might lead to more amyloid beta formation, it may also be related to mutations in apoE and tau protein genes which are characteristic of AD

what is the evidence of these links?

post mortem examination in the brains of elderly people with AD has shown them to be positive for HSV-1 DNA, seropositivity for HSV has also been associated with the development of AD which doesnt necessarily mean its the cause but could be some correlation/co-development, reactivation of HSV-1 in the CNS has been suggested to be the main connected btw HSV-1 infection and AD development triggering the inflammation process, causing damage o the cells along with amyloid plaques and neurofibrillary tangles (marks AD)

HSV-1 correlation with ApoE

neuroblastoma cells infected with HSV-1 also make hyperphosphorylated tau protein, some thought that individuals with HSV-1 may have some change to abnormal processing cause the immune system is trying to get rid ofHSV-1 which could mean some kind of misidentification, ApoE seems to have a strong correlation with HSV-1 lip infection in the peripheral nervous system, with the E4 allele being present in 60% of those infection

ApoE4

associated with an increased risk of having alzheimers, its best to have the E3 allele

zika virus

mosquito born virus that is mostly found in latin america + the carribean, infected individuals can often be asymptomatic or only have mild symptoms, and there are reports linking ZIKV infection to fetal and newborn microencephaly + serious neurological complications like guillain barré syndrome which affects the nervous system, uganda sick primates identified with infection by virus in the zika virus, its genus flavivirus so its a + sense ss RNA virus, other types that are similar include dengue and yellow fever

zika virus outbreak

it can also cross developmental barrier + infect the fetus, the outbreak started in brazil, typical symptoms include rash, pain, maculopapular rash and conjunctivitis, there are also reports of microencephaly and guillain barre syndrome with the virus

microencephaly causes

chromosomal abnormalities, cerebral anoxia (decreased O2 to the fetal brain), infections of the fetus during pregnancy like toxoplasmosis, CMV, measles and chickenpox, exposure to drugs, alcohol or other toxic chemicals in the womb, severe malnutrition and uncontrolled PKU in the mother being a lack of metabolic control resulting in lack of energy transfer to the developing fetus

how is microencephaly diagnosed?

first trimester screening involves combo of tests between week 11 to 13, maternal blood screen measuring human chorionic gonadotropin (hCG) and pregnancy associated plasma protein (PAPP-A0, if protein levels are abnormally high or low, there could be a chromosomal disorder in the baby, ultrasound screen typically looks for extra fluid behind the baby’s neck, increased fluid found on the ultrasound is typically associated with either a chromosomal disorder or heart defect

diagnostic tests

if the result of a screening is abnormal, doctors usually offer more tests to see if birth defects or other problems with the baby are present, these tests are also offered to women with high risk pregnancy (older), women who have had a previous pregnancy affected by a birth defect, who have chronic disease like lupus, diabetes or epilepsy or women who use certain medications

amniocentesis

cells in the amniotic fluid can be tested for chromosomal disorders, such as trisomy 21 and genetic problems, like cystic fibrosis or tay sachs disease while fluids are measured for proteins which are some of the cells released in amniotic fluid from the developing fetus

alpha-fetoprotein (AFP)

a protein the unborn baby produces, high levels of AFP may indicate that the baby has a defect indicating an opening in the tissue like a neural tube defect such as spina bifida or anencephaly or a body wall defect like omphalocele or gastroschisis

acetylcholinesterase (AchE)

its an enzyme that can pass from the unborn baby to the fluid surrounding the baby if there is an opening in the neural tube, this normally isnt released in an intact neural tube

microencephaly

most likely get it in combination with a chromosomal disorder or some kind of metabolic condition, its often an isolated condition, it can occur with no other major birth defect or it can occur in combination with other major birth defects, its defined as a head circumference measurement that is smaller than a certain value for babies of the same age and sex, its usually less than 2 SDs below avg

what are the consequences of microencephaly?

its very common in brazil, it causes seizures, developmental delay like problems with speech or other developmental milestones like sitting, standing and walking, intellectual disability (decreased ability to learn and function in daily life), problems with movement and balance, feeding problems like difficulty swallowing, hearing loss and vision issues

guillan barre syndrome

some ppl with microencephaly develop it, possibly an auto-immune disorder, weakness and tingling in extremities are usually the first symptom, in some instances it may result in paralysis, it is often preceded by an infectious illness like respiratory infection of the stomach flu

guillan barre syndrome types

acute inflammatory demyelinating polyradiculoneuropathy (AIDP), miller fisher syndrome (MFS), acute motor axonal neuropathy (AMAn) and acute motor sensory exonal neuropathy (AMSAN)

how does zika impair brain development?

it can cause neural stem cells to die via apoptosis, mainly radial glial and progenitor cells that die

links btw ZIKV infection and microencephaly

found to preferentially target neural progenitor cells, studies employing neurospheres and cerebral organoids have also demonstrated the susceptibility of NPCs and radial glia to infection, direct infection of E15 mouse brain resulted in high concentrations of ZIKV in radial glial rich ventricular zone