Developmental Biology Quiz

Lecture 5: Neurodevelopment

• Neurodevelopment refers to changes in specific brain properties over time.
• A developmental trajectory describes the typical rate of change in a group.
• Abnormal trajectories are frequently linked to impairments.
• Prenatal neurodevelopment has five stages.
• The first stage is the induction of the neural plate in the embryo.
• The second stage is the process of developmental neurogenesis.
• The third stage involves neuronal migration and aggregation.
• The fourth stage includes axon growth and synapse formation.
• The fifth stage is neuronal death and synapse elimination.
• Fertilization begins when a sperm fertilizes an egg, creating a zygote.
• A blastocyst implants around 7-10 days post conception.
• At 18 days after conception, the embryo has three layers: ectoderm, mesoderm, and endoderm.
• Stem cells in the neural plate have self-renewal and pluripotency characteristics.
• These stem cells differentiate, lose their pluripotency and become unipotent.
• The neural plate folds to eventually form a neural tube.
• The tube's center becomes the ventricular system and spinal canal.
• The anterior portions form the midbrain, hindbrain, and forebrain, in that order.

Developmental Neurogenesis

• Progenitor cells multiply, increasing the neural tube's thickness
• Neurogenesis happens in several zones, including the ventricular zone (VZ).
• Most neurogenesis concludes before birth.
• Some cells retain the ability for neurogenesis after birth.

Neural Migration

• Neurons migrate to their target locations.
• Migration occurs in an inside-out pattern.
• Types of migration include tangential and radial migration.
• The ventricular zone produces excitatory neurons (80% of cells).
• Ganglionic eminences make inhibitory neurons (~20% of cells).

Aggregation

• Neurons in the same area physically align with one another.
• Cell adhesion molecules (CAMs) are crucial.
• Gap junctions, especially in glial cells, are prevalent initially.

Axonal Growth

• Axons grow towards their target cells.
• The axon's growth process involves a growth cone.
• Growth cones use filopodia for exploring their environment
• Filopodia search for appropriate chemical cues.
• Chemoattractive and chemorepulsive cues guide the growth cone.

Growth Cone Mechanisms

• Motor proteins aid in moving materials within the growth cone.
• Vesicle fusion adds membrane to the leading edge of the filopodium
• Actin polymerization pushes the filopodium toward its target

Axon Guidance

• Axonal growth is guided by chemoaffinity hypotheses.
• Target cells release specific chemicals that attract corresponding axons.
• Axons are responsive to different chemical concentrations depending on position.
• Other mechanisms involve topographical projection and chemical gradients.

Synapse Formation

• Synaptogenesis, or the formation of new synapses, follows axon growth.
• Glial cells, such as astrocytes, are crucial during synapse development.
• Initially, the synapse number is greater than necessary.
• Synaptic elimination, where weaker synapses are removed, occurs.
• The remaining stronger synapses determine neuronal connections.

Neuro-muscular Junction

• Axons can lose some synapses while strengthening others.
• Maturing neurons have fewer but more elaborated connections.

Synapse Failure

• Synapse failure leads to cell death via lack of chemical signaling.
• Neurotrophic factors are communicated through retrograde signaling (Cell B-> Cell A).
• Neurotrophins support neuron survival through intercellular communication.
• Competition between terminals for limited neurotrophins may occur.
• Apoptosis is a more organized form of cell death, where cell contents are packaged for removal.
• Necrosis is an uncontrolled cell death form that may cause inflammation and tissue issues.
• Micro-glial cells are important during synapse elimination for cleanup and tissue organization.

Cell Death and Adult Neurogenesis

• Cell death (e.g. through apoptosis) is a normal phenomenon during development.
• Many neurons are lost in early development.
• Most of the CNS doesn't regenerate many new neurons after birth.
• Some exceptions exist.
• Increased rates of neurogenesis are mainly related to early development rather than adult phases.

Developmental Periods

• Critical period: Time for an experience necessary for proper development of neural structures.
• Sensitive period: Time where experience has a greater impact on development, typically earlier, than later in life.
• Both periods indicate high levels of neural plasticity at certain phases.

Critical Period: Example

• Animals show sensory impairments when early development is affected by experience deprivation.
• Early interventions generally show better outcomes than later interventions, especially in children with learning or developmental issues.

Sensitive Periods for Language

• The crucial period for language learning occurs early in life (ages 3-7).
• Language acquisition becomes much harder after ~18 years of age.
• Factors like motivation and immersion vary sensitivity to the language during learning phases.

Why do these periods end

• Myelination physically limits new growth
• Myelination releases factors like Nogo to hinder axonal expansion

Sensitive Periods—Conclusion

• The existence of sensitive periods stems from both biological and non-biological factors.

3 – Adult Neurogenesis

• Neurogenesis, the generation of new neurons, is limited in the CNS.
• Neurons, once lost are permanent losses, typically not replaceable.
• Major production of new neurons happens primarily during development.

Neurodevelopmental Disorders (NDDs)

• NDDs are developmental disorders.
• Symptoms appear early, often affecting cognition and behavior.
• Genetic factors and environmental factors play important roles, as well as possible diagnostic considerations. acquired disorders emerge later in life, as a result of brain injuries or diseases.
• NDDs such as schizophrenia, autism spectrum disorder, and ADHD are commonly seen.
• Psychiatric disorders such as anxiety disorders, depression and others, are also possible comorbidities with NDDs.

Schizophrenia

• Schizophrenia (SZ) impacts about 1% of the population globally.
• Characteristics of schizophrenia include: negative symptoms, both positive and negative symptoms and cognitive symptoms.
• Neural features of SZ include cortical atrophy, abnormal cell organization, hypofrontality, and DA transmission alterations.

Major Risk Factors for Schizophrenia

• Environmental factors can increase SZ risk (e.g., prenatal/postnatal health, social, environmental circumstances, economic circumstances.)
• Genetic and early-life environmental risk factors have an elevated impact on SZ incidence.
• Substances like cannabis are associated with increased risk and earlier onset of schizophrenia among users

Dopamine (DA) Hypothesis of Schizophrenia

• Higher DA metabolite levels (HVA) and an increased number of D2 receptors are hypothesized to cause some SZ symptoms.
• Positive symptoms, like those seen with stimulant drug use, may be linked to increased DA levels.
• Drugs that block DA signaling (e.g., haloperidol) often reduce positive symptoms.

Dopamine Pathway Differences in Schizophrenia

• The mesolimbic pathway is associated with increased DA activity and positive symptoms.
• The mesocortical pathway is associated with decreased DA activity and negative/cognitive symptoms.

Antipsychotic Drugs

• Antipsychotic medications primarily work by blocking D2 receptors.
• Newer antipsychotics are designed to be less indiscriminately selective and have fewer undesirable side effects by targeting other neurotransmitter pathways.

Autism Spectrum Disorder (ASD)

• The spectrum of ASDs show varied symptoms in severity.
• Autism involves difficulties with social interaction, communication, and repetitive behaviors.
• A high proportion of cases involve above average IQ in some areas
• Diagnosed rates are rising due to improved diagnostic methods and increased public awareness.
• Children with ASD show synaptic density that are significantly greater than those without ASD, and these are maintained across development timelines.

Attention-deficit/hyperactivity disorder (ADHD).

• ADHD is a common neurodevelopmental disorder.
• Characterized by inattention, hyperactivity, and impulsivity.
• Symptoms vary in prominence, and often emerge in childhood at the same time as these other NDDs.
• Symptoms of ADHD can affect both children and adults, impacting social, emotional, and developmental health.
• Neurological features of ADHD include reduced total cerebral volume, and delayed cortical maturation, particularly in the prefrontal cortex (PFC). Low DA is also a possible factor.
• Medications like stimulants and non-stimulants address ADHD symptoms, by increasing noradrenergic or dopaminergic neurotransmitter transmission.

More on NDDs

• Co-morbidity, the co-existence of multiple NDDs, is common.
• Several factors affect NDDs, including the overlap in genetic factors between disorders, environmental factors as well as possible issues with diagnostic considerations.
• Psychopathy and anti-social personality disorder are discussed.
• Mechanisms for NDDs include differing genetic factors, developmental trauma and environmental influences.
• A low arousal theory that explains some aspects may be applicable to ASPD as well.