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Questions and Answers
What is the primary function of the SCN9A gene?
What role does Piezo1 play in cell sensitivity?
Which condition is characterized by the incomplete closing of the backbone and membranes around the spinal cord?
What distinguishes Mrgprs in the context of itch sensation?
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Which layer of the gastrula develops into the nervous system?
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What happens to Piezo2 variants that result in a loss of function?
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What is the sequence of events during neuronal development?
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What mechanism does RNA interference (RNAi) utilize?
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During brain development, how many neurons are typically involved?
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What triggers ectodermal cells to become neural tissue?
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What type of receptor is primarily responsible for sensing the pain and itch sensations?
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Which of the following statements about mechanoreceptors is true?
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What occurs during receptor adaptation when a stimulus persists?
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Which mechanoreceptor is responsible for detecting motion and vibration?
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How are the major sensory modalities in the body represented in the nervous system?
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What is the primary function of thermoreceptors such as TRPV1?
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What type of fiber mediates the first sharp pain sensation?
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What effect does peripheral sensitization have on nociceptors?
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What action do opioids perform regarding pain in the central nervous system?
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What is the role of neuropeptides in neurogenic inflammation?
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What type of neuron transmits somatosensory information to the CNS?
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Which of the following best describes the concept of dermatomes?
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Which characteristic of somatosensation refers to the skin area that can activate a sensory neuron?
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What is the role of BMP inhibitors in neural tissue formation?
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What is the purpose of injecting BrDU in developmental studies?
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Which factor is critical for the survival of neurons post-migration?
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How do neurotrophic factors influence neuron development?
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Which of the following describes the axon growth cone?
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What happens during synaptic pruning?
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What is the significance of the HPA axis in relation to depression?
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What typically occurs in neurons during prolonged exposure to stress hormones?
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In the context of neuropsychiatric diseases, what does anhedonia refer to?
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Which of the following best explains the serotonin hypothesis of depression?
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What is a consequence of impaired neurotrophic factor signaling?
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What is the role of radial glial cells during neurodevelopment?
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Which process primarily establishes neuronal polarity?
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Neural induction can be influenced by which of the following?
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Study Notes
Sensory Coding and Somatosensation
- The five senses are: vision, hearing, smell, taste, and touch.
- Four elementary features of stimuli are: modality, location, intensity, and duration.
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Modality:
- Major sensory modalities are mediated by specific receptor neurons.
- Receptors transduce stimuli into electrical signals.
- Chemoreceptors: Responsible for smell, taste, and pain.
- Photoreceptors: Responsible for vision.
- Mechanoreceptors: Responsible for touch, hearing, balance, and proprioception.
- Sensory modalities have discrete anatomical pathways that terminate in unimodal nuclei in the central nervous system (CNS).
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Location:
- The location of a stimulus is conveyed through the receptor's receptive field.
- In somatosensation, the receptive field is the skin area or domain that can activate a sensory neuron.
- The location of a stimulus is conveyed through the receptor's receptive field.
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Intensity:
- The firing rate of sensory neurons conveys information about stimulus intensity.
- As stimulus intensity increases, the frequency of impulses increases while the size and shape remain similar.
- Some receptors adapt to persistent stimuli.
- Rapidly adapting receptors: Detect the onset and offset of a stimulus.
- Duration: The duration of a stimulus is encoded by changes in firing rate over time.
Somatic Sensation
- Includes pain, itch, and temperature.
- Peripheral nerve stimulation activates different types of nerve fibers.
Touch and Proprioception
- Mediated by mechanoreceptors.
- Muscle spindles: Are the principle receptors for proprioception.
Pain and Itch
- Pain and touch are mediated by different neural circuits.
- Nociceptors: Responsible for pain and itch.
- Somatosensory information enters the CNS through cranial and spinal nerves.
- Dermatome: Skin and deeper tissue innervated by a single spinal/cranial nerve.
The Tactile Pathway
- Begins at the receptor endings and travels through afferent pathways to ganglia, then to the dorsal column of the spinal cord, medulla (brain stem), thalamus, and finally to the primary somatic sensory cortex.
Mechanoreceptors
- Four types of mechanoreceptors responsible for touch: RA1, SA1, RA2, and SA2.
- RA1 and RA2: Rapidly adapting, sensitive to motion and vibration.
- SA1 and SA2: Slowly adapting, detect pressure, form, and object shape.
- Type 1 mechanoreceptors innervate the superficial skin layer.
- Type 2 mechanoreceptors innervate the dermis and deeper skin layer.
- Mechanoreceptor transduction: Mechanical energy distorts channels, opening pores and transducing energy into electrical signals.
- If the receptor potential crosses the threshold, an action potential is generated.
- The larger the diameter of the nerve fiber, the faster the action potential conduction speed.
- Meissner corpuscles: Rapidly adapting, located in the superficial skin, responsible for touch.
- Merkel cells: Slowly adapting, located in the superficial skin layer, responsible for touch.
- Pacinian corpuscles: Rapidly adapting, located in the deeper skin layer, responsible for vibration and pressure.
- Ruffini endings: Slowly adapting, located in the deeper skin layer, responsible for stretch.
Nociceptors
- Sense chemical, thermal, and mechanical stimuli.
- Ao fibers (first pain): Responsible for sharp, transient pain.
- C fibers (second pain): Responsible for dull, longer-lasting pain.
- TRPV1: First identified thermal receptor.
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Capsaicin: Activates TRPV1 receptors, eliciting a burning pain sensation.
- HEK293 cell lines are used to examine the sensitivity of sensory neurons to capsaicin.
- Calcium imaging is used to measure neuronal activation.
- Increased calcium levels often correlate with neuronal activation.
Sensitization
- Tissue damage can cause peripheral and central sensitization.
- Hyperalgesia: Enhanced pain sensitivity, where normal touch can induce pain.
- Nociceptors use glutamate and neuropeptides as neurotransmitters.
Neurogenic Inflammation
- Activation of nociceptors induces neurogenic inflammation characterized by redness and swelling.
- Vasodilation: Dilation of blood vessels caused by CGRP (calcitonin gene-related peptide).
- Plasma extravasation: Fluid leakage out of capillaries caused by substance P.
- Neuropeptides activate immune cells, enhancing inflammation and neuronal responses.
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Peripheral insult induce spinal neuron sensitization:
- NGF (nerve growth factor) is upregulated in inflamed tissue.
- NGF-neutralizing molecules provide pain relief.
- NGF increases the excitability of nociceptors.
- NGF is transported retrogradely to the nucleus through signaling endosomes.
- Increased BDNF (brain-derived neurotrophic factor) transcription.
- Central release of BDNF.
Pain Piezos and Itch
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Descending control of pain
- Pain is subjective.
- Pain perception depends on various factors: attention, expectation, gender, and culture.
- Mechanical sensors can inhibit pain signals in the pain circuit (gate theory).
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Over the counter (OTC) pain relievers:
- Inhibit prostaglandin production.
- Prostaglandins induce pain, fever, and inflammation.
- Tylenol, Aspirin, and Ibuprofen inhibit COX enzymes, which catalyze prostaglandin synthesis.
- Lidocaine (local anesthetic):
- Blocks voltage-gated sodium channels.
- Nav1.7, Nav1.8, and Nav1.9 are the main sodium channels in sensory neurons.
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Central anesthetic: Opioids.
- Opioids interact with specific receptors in the CNS.
- Increase potassium conductance and hyperpolarize the membrane.
- Inhibit calcium channels, preventing neurotransmitter release.
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Congenital insensitivity to pain:
- Inhibits the ability to perceive physical pain.
- Individuals can distinguish between sharp and dull, or cold and hot stimuli, but cannot sense burning sensation.
- Often associated with peripheral neuropathy.
- Caused by mutations in the SCN9A gene, which codes for a subunit of the sodium channel.
- Without functional sodium channels, pain signals cannot be transmitted to the brain.
Piezos
- Piezos are mechanically activated ion channels.
- Identified using RNAi screening in a mechanically sensitive cell line (Neuro2A).
- Piezo1 is required for mechanical sensitivity in Neuro2A cells.
- Piezo1 overexpression in mechano-insensitive cells (HEK293T) confers mechanical sensitivity.
- Identified using RNAi screening in a mechanically sensitive cell line (Neuro2A).
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Piezo2 variations:
- Loss-of-function mutations lead to:
- Decreased discriminative touch perception.
- Decreased proprioception.
- Ataxia (uncoordinated movements).
- Dysmetria (inability to accurately judge distances or target movements).
- RNAi: RNA molecules inhibit gene expression or translation by interfering with targeted mRNA molecules.
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Mechanosensation in Merkel cells:
- Piezo2 functions as a mechanical sensor.
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Mechanosensation in sensory neurons:
- Piezo2 functions as a mechanical sensor.
- Piezos mediate mechanical sensation in vitro and in tissues.
Itch
- Itch is a distinct sensory experience from pain.
- Anti-malarial drugs like chloroquine (CQ) induce itch.
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Mrgprs (Mas-related G protein-coupled receptors) mediate non-histaminergic itch:
- Expressed in small-diameter neurons.
- Deletion does not affect acute pain sensation but blocks CQ-induced itch.
- CQ directly activates DRG sensory neurons to induce itch, and this response depends on Mrgprs.
- GPRR: Is required for mediating itch sensation, not pain.
Neurodevelopment
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Anencephaly: A birth defect where the baby's head is not fully developed due to damage during early brain development.
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Spinal bifida: A birth defect where the backbone and spinal cord do not close properly.
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Neural development:
- Underlies much of behavioral development.
- Influenced by environmental factors that affect nervous system changes.
- Patterned by early developmental events.
- Neural progenitor cells at different locations produce distinct neuron types.
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General features of brain development:
- 100-200 Billion neurons form millions of synapses.
- Epigenesis - developmental course where things go from general to specific.
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Stages of brain development:
- Zygote: Fertilized ova, cells begin to divide (cleavage).
- Morula: Solid ball of ~100 cells.
- Blastula/Blastocyst: Solid ball with a fluid-filled center.
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Gastrula: Ball inverts upon self, forming layers:
- Endoderm: Internal organs.
- Mesoderm: Skeleton, muscles, and circulation system.
- Ectoderm: Skull, nervous system, and skin.
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Notochord: Induces the ectoderm to become the primitive nervous system.
How does the ectoderm know to become neural tissue?
- This is a complex question that is still being researched. Several signaling molecules and genetic pathways are involved, but the precise mechanisms are still being elucidated.
Neural Induction
- Organizer - specialized group of cells that control the differentiation of the neural plate from the ectoderm.
- Signals from the organizer region can induce a second neural tube.
- BMP signals from the organizer region induce neural tissue.
- BMP inhibitors, like noggin, and chordin, secreted from the organizer region bind to BMPs, preventing epidermal formation.
- Proteins like noggin and chordin induce neural tissue development.
Neurulation
- Neurulation starts around day 21 and ends by day 28.
- The nervous system is highly patterned as a consequence of early developmental events.
- Neural tube regionalization is evident in the 3-vesicle and 5-vesicle stages.
- Morphogens - signals that can direct patterning and different cell fates based on their concentration.
- Wnts and Wnt inhibitors - secreted by mesodermal and endodermal cells around the neural plate.
- Cells in anterior and posterior regions of the neural plate express different transcription factors.
Neurodevelopment
- Neuroepithelial cells - neural stem cells which give rise to new cells, form the ventricular zone.
- Radial glial cells (RGCs) serve as neural progenitors and structure scaffolds.
- RGC nuclei migrate along the apical-based axis as they progress through the cell cycle.
- RGCs undergo cell cycle and mitosis to generate neurons and glia.
- Post-mitotic neurons - newborn neurons that do not go through the cell cycle.
- Newly generated cells migrate away from the ventricular zone using RGCs.
- Central neurons migrate along glial cells and axons to reach their final target.
Neuronal Differentiation
- Cells become specialized.
- Over 200 types of neurons with varying morphology, receptors, and neurotransmitters.
- Neuronal differentiation is determined genetically and by local molecules.
- The targets of neurons determine their neurotransmitter.
- Excitatory and inhibitory neurons are derived from different proliferative zones.
- Neurotrophic signals from a neuron’s target regulate its survival.
- Neurotrophic factors - secreted by target cells and critical for neural survival.
- Neurotrophin hypothesis: cells near the target of a neuron secrete small amounts of an essential nutrient or trophic factor.
- Neurotrophins - a family of proteins important for the survival, development, and function of neurons.
- Neurotrophic factors bind to specific receptors and are transported to the cell body to promote neuronal survival via retrograde signaling.
- Different neurotrophic factors promote survival of distinct populations of neurons and induce intracellular signaling pathways.
- Low or lack of neurotrophic factors leads to neuronal death via apoptosis.
- Apoptosis - programmed cell death; highly regulated and controlled.
- Necrosis - traumatic cell death resulting from acute cellular injury.
- Death signal - cell stress, such as DNA damage and anoxia.
- Neurotrophic factors suppress caspase activation and cell death.
Axon Outgrowth and Synapse Formation
- Differences in molecular properties of axons and dendrites emerge early in development.
- Neuronal polarity - distinction between axons and dendrites; established through rearrangements of the cytoskeleton.
- Axon marker: Tau.
- Dendrite Marker: MAP2.
- Axon specification is key in neuronal polarization.
- Signals from newly formed axons suppress the generation of additional axons and promote dendrite formation.
- Both intrinsic and extrinsic factors determine neuronal morphology.
- Cytoskeleton - forms the basis of neuronal polarity and directs intracellular trafficking.
- Microtubules - structural components of dendritic trunks and axons, highways that mediate long-distance transport in neurons.
- F-actins - direct local traffic, accumulate in axon terminals and spines.
- Growth cone - specialized structure at the tip of an axon.
- Axons are guided by chemical gradients of attractants and repellents.
- Various signaling molecules control the growth and guidance of developing axons.
Synaptic Pruning
- Most synapses are made by two years old.
- Regression occurs during the next three years.
- Benefits of polyneuronal innervation of immature muscle:
- Ensure every muscle fiber is innervated.
- Allows all axons to capture a target.
- Synaptic elimination provides a way to refine synaptic connections.
- Competitive synapse elimination shapes connectivity.
- Sensory inputs are critical for neurodevelopment.
- Broad tissue arbors become denser and focused.
- Molecular cues control initial specificity; neural activity sharpens specificity.
- Cell-cell contact differentiates into specialized pre- and postsynaptic terminals.
- Synapses undergo major rearrangements to mature (synaptic elimination and synaptic strengthening).
Neuropsychiatric Diseases
- Depression - persistently depressed mood or loss of interest in activities, causing significant impairment in daily life.
- Hypofrontality - reduced activity in the prefrontal cortex.
- Chronic stress can impair frontal cortex function, contributing to depression.
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HPA Axis - amygdala activity increases CRF, hippocampal and frontal activity reduce CRF.
- Corticotropin-releasing factor (CRF)
- Adrenocorticotropic hormone (ACTH)
- Stress Hypothesis of Depression - prolonged corticosterone exposure impairs frontal cortex dendritic spine stability.
- Anhedonia - inability to feel pleasure from typically rewarding events.
- Sucrose consumption test - measures anhedonia, a symptom of depression.
- GC-induced loss of prefrontal dendritic spines is associated with depression-like behavior.
- Heterozygosity of cytoskeletal supporting genes impairs resilience to (subthreshold) elevation of GCs.
- In depression, serotonergic innervation from the raphe nucleus is often reduced.
- Serotonin hypothesis of depression - diminished activity of serotonin pathways is a possible mechanism in the pathophysiology of depression.
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