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THIRD MODULE - Coggle Diagram

- - - - glutamate released from hypoxic acons
        
        treatment = AMPA and NMDA receptor antagonists
      - vulnerable to free radical attack
        
        free radical scavengers / antioxidants
      - low levels of antioxidant enzymes make oligodendrocytes and VTA dopamine neurons vulnerable
  - - - 2003 study: O4+ve most abundant in PN2 rat brain
      - 2008: ligated CCA in PN6 and less oxygen. treated with memantine (NMDA receptor). RESULT: increased O1 staining with treatment
      - 2012 study looked at treatments of UDP-glucose, GDNF, memantine
        
        all three decreased white matter pathology
        
        and resulted in less motor dysfunction in hindlimbs
  - - - ex 1: O4+ve cells = decreased
      - ex 2: amount of cerebral myelin = decreased
      - ex 3: short term memory in radial army maze = more errors
      - ex 4: hyperactive but not inattention
      - ex 5: long term effect on myelin showed decreased surface area
    - - from SNC to striatum
      - from VTA to cerebral cortex
      - 2007 model to rescue O4+ve and dopamine neurons investigate free radical scavanger (melatonin) and glutamate receptor antagonists
        
        clinical relevance becuase premature infants have long period of intrinsic deficiency
      - also could be do to increased inhibition by GABAergic input to VTA DA neurons
        
        2019 study investigate GABAergic synapses that innervate the VTA DA neurons: significant increase in length and thickness of postsynaptic density
        
        larger PSD = increased inhibition of VTA DA neurons. this increased inhibition could contribute to cerebral hypodopaminergia
        
        schizophrenia = hyperdopaminergia
        
        schizophrenia arises developmentally
        
        maternal immune activation is a risk factor for schizophrenia in the offspring
        
        investigated synaptic innervation of midbrain dopaminergic neurons found marked decrease in volume of presynaptic terminals and volume and length of PSD of RMTg GABA - VTA dopaminergic synapses
        
        major injury site in schizophrenia is considered to be presynaptic including the VTA
  - - - very premature babies not good at temperature change
- - - - cholinergic interneurons although few in number have a large enough axonal arbour which allows them to interact with SPNs at a distance to facilitate in fine tuning of movement.
        
        in basal ganglia, EPN and SNR are inhibited which leads to disinhibition of motor thalamus and parafiscular nucleus this leads to depolarisation of ACh interneurons
        
        ACh role comes to play after SPNs have already fired and become hyperpolarized. release of ACh brings SPNs RMP closer to the action potential threshold which in a way is resetting them in preparation for the next required fine-tuning of movement
      - REPOLARISE inhibited SPNs for next specific fine-tuning of movement::::::
    - - RMP close to action potential threshold meaning very easy for ACh neurons to fire/depolarise yet have long afterhyperpolarisaiton
        
        AHP means pause which is reward related
  - - - SOMs released at SPNs that need to be activated for a movement
      - at same time release NO near capillaries of firing SPNs = increases blood flow (VASODILATION)
        
        NO also inhibits those SPNs not required for the specific movement
      - at same time NPY released near the inhibited SPNs which decreases blood flow (VASOCONSTRICTOR)
  - - - evidence:
        
        anatomical evidence: GABA synapses are on dendrites of SPNs. if fill rat SPN with biocytin the trace shows that SPN synapses with another adjacent SPN
        
        electrophysiological evidence: recording from adjacent SPNs, expect to see IPSP. only 2002 study did and thats because the experimental conditions were different to the others.
        
        IPSP likely to be mediated by GABA
      - 1 SPN may only inhibit 1/5 of SPN so who inhibit the rest
        
        no evidence that gaba/calretinin neurons do
- - - - 3 characteristics: unspecialised, able to divide, able to differentiate into a specialised cell
      - Neuroprotective vs neurorestorative
        
        neuroprotective
        
        aim to prevent the pathological cascades that cause nerve cell death within 24 hour of injury
        
        for perinatal hypoxia: gentle hypothermia, antioxidants, glutamate receptor antagonists (xenon)
        
        limited by short time for induction within 6h of birth so not always clinically achievable
        
        neurorestorative
        
        have a delayed onset for internvention, days after injury
        
        aim to replace dead neurons and restore damaged tissue through the formation of new neurons
      - intrinsic vs extrinsic sources
        
        intrinsic
        
        located in SVZ and SGZ of hippocampus
        
        SVZ cells become olfactory neurons
        
        SGZ cells become neurons in hippocampal dentate gyrus
        
        extrinsic
        
        embryonic stem cells from inner cell mass of embryos
        
        pluripotent - develop to endodermal, mesodermal or ectodermal cells
        
        adult stem cells from post-embryonic differentiated tissue
        
        multipotent - develop to mesodermal cells
      - for perinatal hypoxic brain injury 2 effective are:
        
        neural stem cell / progenitor cells in brain (NSPCs)
        
        isolate subventricular part of brain for immune cell growth which is hard to do
        
        bone -marrow derived mesenchymal stem cells (MSCs)
        
        have earliest clinical impact due to
        
        easier accessibility and harvesting (NSPCs need to be isolated from SVZ)
        
        can be sourced from own patients reserves
        
        do not activate an immune response due to a lack major histocompatibility class II antigens
        
        studies
        
        2010 neonatal mice: injection of MSCs at PN9. measured forelimbs on cylinder test. RESULT: functional improvement and decreased lesion size at 21 days after lesion
        
        2015 study: EFFECT ON STRIATAL SPNs AND MOTOR SKILLS: extracted (from femurs of rat), cultured (increase no.s through cell division) and injected MSCs (at P/n14 after PN7 HI. .= motor skills improved at 12 weeks
        
        how does bone marrow derived MSCs restore / help the injured perinatal H/I ?
        
        migrating an neuroblasts which enables differentiation into SPNs
        
        dutch 2011 - MSCs secrete 7 growth factors which modulated the microenvironment to allow neuroblasts to differentiate into SPNs
        
        cameron 2015 showing increased neurons in CPu
        
        2002 - subcutaneous adipose tissue another rich source of MSC
        
        advantages: tissue more easily accessible and available than bone marrow
        
        superior to bone marrow in treatment of ischemic stroke in mice
        
        possibly due to 10% different in secretion profile of growth factors
        
        studies
        
        2009 study showed it protected against striatal and thalamic volume loss
        
        2021 oorschot - AD-MSC day 7 post injury double treatment
        
        did not decrease cell proliferation of SVZ
        
        decreased absolute number of microglia in striatum
        
        decrease striatal inflammation
        
        single treatment could not restore absolute number
        
        1 more item...
    - - mild = decrease temp by 1-3deg
      - moderate = decrease temp by 4-7 deg
        
        fetal sheep study = less neuronal loss in CPu, cortex and hippocampus with cooling following hypoxia
        
        infants had head cooling vs whole body cooling
        
        Cerebal palsy decreased from 36%
        
        did not investigate functional improvement
      - hypothermia in combination with antioxidant treatment
        
        to fully decrease free radical production 2008 oorschot showed at PN14 - normal total number of neurons had been restored
        
        effect on motor skills - used staircase test - deficits in contralateral limb to injury in striatum but full imporvement after treatment
      - hypothermia in combination of xenon
        
        xenon antagonist of NMDA receptor
        
        2008 study = effect on fine motor skills - used staircase test - improved pathology scores but not completely normal
        
        limitation = expensive
        
        piglet study = decreased number of dying cells in CCx and putamen
      - hypothermia in combination with erythropoietin
        
        EP is an anti-excitotoxic, an anti-oxidant and anti-apoptotic
        
        human infants - better 12 month outcomes than hypothermia alone
  - - - less O2 = decreased ATP
        
        ion homeostasis disrupted
        
        effects on acid/base balance - increased lactic acid
      - glutamate toxicity via calcium overload
        
        ATP dependent Na/K nerve cell membrane pump less efficient
        
        high levels of glutamate
        
        postsynaptic neuron dies from calcium overload
        
        influx of Na
  - - - Rice / Vannucci hypoxic ischemic model
        
        3 controls, lesion, hypoxia, and lesion + hypoxia
        
        neuronal loss
        
        gliosis (incrased no. of astrocytes)
        
        abnormal myelination
        
        locomotor problems
- - - - causes:
        
        impaired placental functoining
        
        obstructed umbilical cord around bubs necks
        
        compressed aorta in mother
        
        bleeding from uterus