Lecture 5: Neurodevelopment PDF

Lecture 5: Neurodevelopment Paul Whissell, Ph.D. Behavioral Neuroscience (PSY290) 1 Key Concepts be can...

Lecture 5: Neurodevelopment Paul Whissell, Ph.D. Behavioral Neuroscience (PSY290) 1 Key Concepts be can similar in or Development refers to a Faste slower membares normal change in a specific property same species than of the over time (e.g. brain size) A developmental trajectory refers to the normal rate of change in a group (e.g. brain size in humans) Abnormal trajectories are canhenceinviornmental be often associated with there impairments genetic mostly ou 2 Overview Part 1: Prenatal Development 5 stages Part 2: Postnatal Development after birth Synaptic pruning Developmental periods Neurogenesis Neuroplasticity Part 3: Neurodevelopmental Anomalies Autism Schizophrenia Attention Deficit Hyperactivity Disorder 3 * Prenatal Neurodevelopment test common Q conception 1. Induction of neural plate in the embryo 2. Developmental neurogenesis 3. Neuronal migration + aggregation 4. Axonal growth + synapse formation 5. Neuronal death + synapse elimination 4 1 – The Beginning Begins when the sperm fertilizes the egg, making a zygote divisio & organization Blastocyst implants around 7 – 10d, continues to develop 5 1 – Neural plate ~18d after conception, embryo has 3 layers develops into Ectoderm (outside) nervous syste Mesoderm (middle) Endoderm (inside) Neural plate is on the ectoderm Formation of the neural Neural plate will become the plate is induced by nervous system chemicals from the mesoderm 6 In the Neural plate… brain) Stem cells (not in adult nearly unlimited capacity for self-renewal (in artificial conditions; i.e. culture) pluripotent (can develop into many cell types) any cell Division produces a new stem cell + another cell Cells will eventually lose this capacity, becoming unipotent 7 Over time, the neural plate… Folds to form neural groove Sides of neural groove fuse to form neural tube (~24d) renticul structure beginnings Tube center will become the ventricular system + spinal canal (for CSF) Growths on the anterior of the tube (~40d) later become midbrain, hindbrain + forebrain 8 Divisions of the Nervous System in humans & primitive animals is particularantm ist phase Prenatal Development The Adult Brain 9 2 – Developmental neurogenesis mass neuron production Progenitor cells divide, thickness of tube increases Several neurogenic zones, including the ventricular zone (VZ)* made in & one place moved to another Most neurogenesis concludes before birth, but some cells might retain capacity for NG in adulthood 10 3 – Migration Movement of cells to their target locations Inside-out process (outside layers migrate last) Migration may be tangential or radial (cell type)* 11 Migration V2 Ventricular zone gives rise to excitatory neurons (80% of cells) more complex migration pattern Ganglionic eminences give rise to inhibitory neurons (~20% of cells) in same place end up but come from different (genenerated spaces 12 Aggregation grouping Neurons align with other neurons in the same area > - in right orientation Cell adhesion molecules (CAMs) vital here CAMs are present on the surface of cells Gap junctions (glial cells) prevalent during this period - ↓ no synapses yet 13 4 – Axonal Growth & dendrides Axons grow outward to their targets grow eady processe when only Precise process migrated not random > chemically guided - At the end of each axon I is a growth cone , ↑ finds chemical a it & grows Each cone has filopodia (finger-like extensions) ‘Search’, extend + retract 14 The growth cone actin autokeletone fiber grows outward gradually 15 How does the axon “know where to go?” 16 Sperry’s Exp – Healthy Frog in frog optic nerve requerat can humans crot ↑ eyeissesa kes rotatedGouna It 17 With eye rotation greaminedble with still connected Posignment changes when axons are cut wha+ 'S they still grow back (notclose to original deirgets 18 With eye rotation 19  chemicals Axonal Growth for attracting & repelling 1s t growth grow Small group of pioneer axons moves first, others follow later forming bundles (i.e. tracts; fasciculation) ↳ bundles of axons travel together (efficient) Growth cones responds to various chemical signals towards away · also facilitated Attractants Repellants axons other by the area in 20 21  brain connections Theories of Axonal Dev. (1) First theory = chemoaffinity hypothesis The axon grows toward a specific target because that target releases special chemicals Cell A releases Chemical X Axon B is sensitive to Chemical X but Axon C is not Axon B grows toward Cell A, but Axon C does not However, signaling is likely not quite this simple (not one-to-one or A to B) Evidence is lesion studies 22 Theories of Axon Dev. (2) Normally, there is topographic projection of Retina > Tectum visud pathway If projection is simple (one-to-one) lesion no connection again of an area should prohibit growth of axons ever This is not what happens: If an area loses its normal input, it receives input from other areas instead (top) If an area loses its normal target, it will project to another target instead (bottom) to thing a normal visual processing seritive conc matters ↳ [T 23. Theories of Axonal Dev. (3) Next, we have the topographic gradient hypothesis (updated variation of the first theory) According to this theory, axons are sensitive to the same factors but in different amounts Amount of exposure is determined by the relative position of the axons in the tissue (e.g. retina) Cell A releases Chemical X Axon B and Axon C are both sensitive to Chemical X However, Axon B is exposed to more Chemical X Axon B grows toward Cell A but Axon C does not 24 Theories of Axonal Dev. (4) if you miss a target can You grow new one con drives growth ar 25 Synapse Formation Synaptogenesis (making of new synapses) occurs next, but is less well understood both change at time the same Role of glial cells (e.g. astrocytes) important You form more synapses than you need originally; many synapses created are later removed (in a massive “synaptic elimination” phase) (selected for - > strongest synapses stay weak are eliminated > - 26 At the neuromuscular junction… (also other areas system of nervous An axon may “lose” at some synapses, but “win” at others without neuro connectionnies likely The inputs of a mature neuron are fewer but more elaborate and more effective (i.e. stronger) 27 What if synapses aren’t formed? When two cells are connected via a synapse, they exchange chemical signals This form of signaling is vital to cell survival Cells that do not form synapses will often die 28 What are the survival signals? survival sinnal Neurotrophins are transmitted via retrograde signaling (from Cell B > Cell A) There is a limited amount of NTs released, which leads to a competition among terminals (NT hypothesis) doesn't get key enocor from at 29 Apoptosis v. Necrosis Apoptosis is a form of ‘programmed cell death’ Cleaner process, wherein the cell’s contentsat are packaged from crica for convenient disposal /removed it cell not Less inflammation usetech > t - own on it's dies In necrosis, another form of cell death (e.g. via nutritional insufficiency) the results are different Cells ‘break apart’ + spill their contents More risk for inflammation Microglia play an important role in mitigating inflammation and ‘cleaning up the mess’ 30  messcarily Cell death is normal not a bad thing You generate more neurons than needed (~50% more) Many neurons are lost during early development 50% lost - during development ~ In most of the CNS*, new neurons are not generated in adulthood (some exceptions 31 Review * EXAM know order explain 1. Induction of neural plate & how to in 2 sentance, each 2. Developmental neurogenesis 3. Neuronal migration + aggregation 4. Axonal growth + synapse formation 5. Neuronal death + synapse elimination 32 In the mouse brain Similar order of events proposed in the human brain ne wron product vasculature synapse synapse removal 33 Part 2: Postnatal Neurodevelopment (after birth) 34 Postnatal neurodevelopment learning Synaptic density bases of & memory Synaptic formation Synaptic pruning Developmental periods Critical and sensitive Neurogenesis (generation of new cells) Potential role in learning + memory 35 From birth to adulthood … Volume of brain quadruples (x4) neurn ↳ not more & laculy S Growth not due to a gain in neurons (in fact many neurons are lost), but other processes Synaptogenesis (more synapses) Dendritic arborization (growth of dendrites) Myelination of axons vaculature ruids Some brain areas develop faster than others citical more for early nurive Primary sensory cortices (e.g. visual, auditory) develop early (associated w/vital survival functions for infants) faster development Prefrontal cortex (PFC) develops last development slower ↑ experience rea. later on & needed 36 1) Synaptic density w/age Sensory mature earlier, PFC matures later “Phylogenetically new” mature later particular “Secondary association” mature later munans clow development matures 1st sensory Gogtay et al. 2004. PNAS. 37 Potential consequences The PFC is involved in cognitive control, which is most developed in adulthood kids : more impulsive etc. Mismatch theory (i.e. late development of PFC relative to affective/reward systems) was proposed, but 1 motivatio compelling evidence is lacking development carre · ends) (pruning to ↳ over estimattical number still continues - brain develop · Now viewed as a “neuro myth” or oversimplification Development continues past this point; individual differences in rate (some earlier, others later); misunderstands risk adolescence explore > - & connections make nee 38 Synapse elimination of this isat lack Glial cells play an important role in synapse formation, elimination and maintenance Increasingly, we are considering the role that glial cells might play in disorders of the nervous system 39  usefull Synaptic properties are modifiable with experiences (e.g. learning). This will be the topic of our next class. 40 2 – Developmental periods Critical period: Time interval where an experience must occur for proper development system ↳ visula Sensitive period: Time interval where an experience has a relatively greater effect on development larges beg. to learn when young Ceasier Thought to be periods of high neuroplasticity We can identify potential developmental periods with deprivation and enrichment studies in animals Periods in humans suggested by correlational data* & tragic periods of depravatia 41 Critical Period: Example In animals, sensory disruption when young (e.g. blindfolding, special environments) profoundly impedes brain and behavior in adulthood1 tions conne behavioral less has T outcomes modeled in & at could never see a horizontal lim > - changed behaviour & neurons cats Reverse is true and critical for humans: early interventions are more helpful in children Visual problems (e.g. cataracts) and hearing problems are more easily addressed in children (cannot process Inter on Blakemore and Cooper. 1970. Nature. 42 Sensitive periods for language? 43 Why do these periods end? / finite / special constraints & cells can prohibit future growth Myelination of existing neurons creates a physical barrier to growth and sprouting of other axons Myelination can also release certain factors which inhibit axonal growth, such as Nogo 44 The existence of sensitive periods is not entirely a biological phenomena. not just neuroplarity 45 Sensitive periods for language Language acquisition easiest at 3 – 7 years of age Language much harder to acquire after ~18 years1 environmental features complex Idea that language acquisition becomes much more difficult with age is generally believed, but is quite difficult to test - with also immersion language the Motivation for second language learning is different Context in which second language is learned varies Language acquisition may involve different mechanisms in different ages 1. Hartshorne et al. 2017. Cognition. 46  productio of 3 – Adult Neurogenesis neer cells in In add rare & only in certain part, or brain For the most part, the CNS has limited regenerative capacity for all of brain the all neurons developmental : neurons brain areas make some some adult : Neurons, once lost, are lost forever (and we’re losing them all the time) You can only really make new neurons in large amounts during development – we are thus continuously running out of cells However, there may be exceptions to this rule 47 Adult neurogenesis Generation of new neurons in adulthood Hippocampus Lateral ventricles Larea around to - > attached alfactory system New neurons take time to develop rare study in human 4-6 weeks - extremly invasive Bischofberger. 2007. Nat Neurosci. 48 The neurogenesis debate Neurogenesis occurs in most mammalian species studied but it is currently unclear whether it is meaningful in adult humans1 not as rignificant humans in Assuming it does occur in humans, why does it matter? Learning + mood regulation Snyder et al. 2019. TINS. 49 Why does neurogenesis matter? When young, new adult-born neurons have enhanced excitability and plasticity relative to older, developmentally-generated cells1,2 Enhanced hippocampal neurogenesis is correlated with improved memory and reduced anxiety3 ↳ could be the bases of anti-anxiety meds Young neurons may play a role in stress resiliency, allowing for greater resistance to stress-induced depression4 cells different than are newer older ones ↳theremore plastical a 1. Snyder et al. 2005. J Neurosci. 2. Mongiat et al. 2009. PLOS One. 3. Yun et al. 2016. Nat Med. 4. Snyder et al. 2011. Nature. crew? 50 Part 3: Neurodevelopmental Disorders (NDDs) 51 NDDs Disorders wherein there is abnormal development of the nervous system, leading to abnormal cognition and behavior NDDs often emerge early in life (e.g. autism, ADHD, intellectual disabilities and language disabilities)* High heritability, strong role of genetic factors · befor enviormental factors matter than develop NDDs are considered distinct from acquired disorders, which usually emerge in adulthood and are the result of brain changes (e.g. injuries) in adulthood Traumatic Brain Injury, Alzheimer’s Disease, Multiple Sclerosis and more 52 NDDs but more severe less common 53 Schizophrenia (SZ) 1 % of population 54 Schizophrenia: A Serious Disorder & cognitive brod claster of symtones positive negative , 55 Neural features of SZ not used for diagnosis Cortical atrophy (temporal cortex, HPC and PFC); less gray matter Abnormal cell organization (HPC) all overthe place Hypofrontality less frontal activity Alterations in DA transmission dopamine 56 Major risk factors for SZ penetic & enciormental Prenatal + postnatal risk factors; some are “choices” (e.g. drugs) whereas others are “random accidents” (e.g. illness).-Ainmajor factor worth discussing is cannabis. Iyegbe et al. 2014. SP. preque risk factor for 52 Sullivan 2005. PLoS Med. mother 57 Cannabis during developmentassociated with changes in the brain that resemble/overlap with SZ · long term use ↳ may I risk in varnable individul (x2 more risk) Heavy cannabis use during adolescence is a concern as it may impede brain development during a vital sensitive period Cannabis use is associated with an increased risk for schizophrenia (~2x) and an earlier onset1,2 Other drugs might be involved (nicotine/smoking) Earlier onset of cannabis use is associated with more significant impairments in cognitive functioning 1. Moore et al. 2007. Lancet. 2. Di Forti et al. 2014. Schizo Bull 3. Broyd et al. 2016. Mol Psychiatry. 4. Long et al. 2012. BMC Neurosci. 58 Adolescent cannabis + the brain White matter integrity reduced one of the least dengreus drug C saver than alcohol) Gray matter reduced in HPC + OFC (like SZ) Hippocampus Orbitofrontal cortex 1. Gruber et al. 2014. Psychopharmacol (Berlin). 2. Matochik et al. 2005. Drug Alcohol Dependence. 3. Fibley et al. 2014. PNAS. 59 dopamine DA hypothesis of SZ Higher levels of DA metabolites (HVA) more active pathways More D2 receptors Positive symptoms are similar to the effects of drugs that increase DA signaling (e.g. amphetamine, L- Stimulants DOPA) Positive symptoms reduced by drugs that block DA signaling (DA antagonists; antipsychotic drugs such as haloperidol) 60 Dopamine Hypothesis of SZ DA mostly explained by one pathway Higher DA activity in mesolimbic pathway (positive symptoms ↳target by most Drugs Lower DA activity in mesocortical pathway other symptope Psychopharmacology Institute. 2016. 61 Antipsychotic drugs Most antipsychotics block D2 receptors traditional autosychotic ↳ work for most Conventional antipsychotics are relatively selective in this action, atypical antipsychotics (clozapine, risperidone) block other targets (e.g. 5-HT2 receptors) ↳ best in let common forms 62  Cumulative evidence suggests that schizophrenia is a heterogenous the disorder. mari disorder ↓ nave many forms diff symtomes 2) Alnaes et al. 2019. JAMAP. We will return to this point in L10. 63  newly acknowledged Autism (on TV) abilities in reality it rarley commes with inhance cognitive 64 Autism – Symptoms & severities varie symptomes Poor social interaction Fails to respond to name, poor eye contact, resists cuddling, prefers playing/being alone May not recognize/respond to social cues Repetitive behaviors Arranging objects, making sounds, hand flapping, head rolling and body rocking Inability to switch between behaviors easily · special interests Slow language development >2 years, repeat with words/phrases, abnormal tone/rhythm 65 Autism - Spectrum - symtomes emerge early Heterogeneous group of disorders, defined by a set of symptoms varying in severity p 10% of cases 66 Autism - Epidemiology ~1% population, more common in boys (~3:1)* ↳ not representitie ↑ masks & & · rates ↳ Girls more likely to more force to behove normally Increase in diagnosis is associated w/increased awareness, increased parental age + more sensitive diagnostic procedures 67  ASD + synaptic density In ASD, synapse number is higher in childhood and remains higher throughout adulthood Greater cortical expansion in specific areas may predict ASD risk1 more spires Hazlett et al. 2017. Nature. 68 Attention Deficit Hyperactivity Disorder (ADHD) 69  hyperactive ADHD clusters : innatentive & Two main symptoms which may manifest differently In the case of inattention, many examples: Lack of attention to details or careless mistakes Does not seem to listen when spoken to directly In the case of hyperactivity/impulsivity: Excessive fidgeting Running, climbing, restlessness in inappropriate situations Three forms (combined form + 2 predominant forms) rate has gone up 70 ADHD 6 – 10% of the population Recent data suggests rates are increasing over the past few decades Xu et al. 2018. JAMA. 71 Neural features of ADHD Reduced total cerebral, PFC, BG, dACC + cerebellum volume T les developed & smaller Delay in cortical maturation, prominent in the PFC Lower white matter volumes (corpus callosum) dopamine Lower DA levels (reward deficiency theory) Changes in the PFC are thought to be central to the disorder and its treatment with drugs Curatolo et al. 2010. IJP. 72 Drug treatments for ADHD stimulants Most of these drugs work by increasing dopaminergic or noradrenergic transmission in different ways Common treatment is with stimulants like amphetamine and methylphenidate (mechanism is primarily NA and DA transport inhibition) receptors directly target more Non-stimulants for ADHD are also available, such as atomoxetine (targets NA transport), guanfacine and clonidine (which target α2 receptors) Faraone et al. 2018. NBR. 73 Normalizing DA levels Mugbenticial if somone has the disorder lowly not in ppl without instead other ↳ more to extrane 74 More on NDDs overlap Co-morbidity is common; people with one NDD are at much higher risk for having another Odds of autism and ADHD together (~20/10 000) are much higher than expected by chance (~1/10 000) Co-morbidity may be due to similarities in genetic factors or environmental factors (as well as issues with diagnostic methods) dignostic difficulties or tribut onottiproper Past research has suggested NDDs are much more common (ADHD, ASD) or more severe (SZ) in males More recent research challenges this view and suggests diagnostic and cultural biases might contribute to rates Many disorders show some disparity (e.g. anxiety, depression and pain more common in females) Hansen et al. 2018. NJP. 75 Psychopathy and anti- social personality disorder A not traditional NDD 76 Psychopathic personality Includes a constellation of traits: guiltless, manipulative, charming, callous, self-centered Aware of problematic behavior to Often poor self-control and low empathy supertica Research is difficult to do (privacy concerns) and biased (focuses on individuals who are incarcerated) Limited studies of psychopathic traits elsewhere1 Borgoholthaus et al. 2023. JPID. 77 Mechanisms Argued to be a form of NDD1 Early trauma/exposure to violence + brain damage (OFC) and poor parental relationship are risk factors2,3 Genetic risk factors also exist4-6 Personality disorders and psychopathic traits* are heritable MAO and 5-HTTLPR may be involved* Brain changes in ASPD: Reduced function, volume, and connectivity in the FC + amygdala7 1. Raine et al. 2018. ARCP. regulating emotional 2. Craparo et al. 2013. EJP. 3. Gao et al. 2010. Psychol Med. processing maly be 4. 5. Blonigen et al. 2005. Psychol Med. Tiihonen et al. 2019. Mol Psychiatry. different 6. Sadeh et al. 2013. JAP. 78 https://www.ted.com/talks/jim_fallon_exploring_the_mind_of_a_killer/transcript?language=en 7. Umbach et al. 2015. JCJ. Low arousal theory threat Inappropriate ANS reactivity to Chronic state of “stimulus hunger” (characteristic of ADHD, may be involved in ASPD) Indicators of emotional state abnormal in ASPD Low resting heart rate and electrodermal activity Abnormal response to threatening stimuli May affect ability to learn from punishment Umbach et al. 2015. JCJ. Kavish et al. 2017. PQ. Fowles. 1980. PP. 79