Unit 2 Neuro Notes PDF

Sensory coding and Somatosensation: 5 senses: ○ Vision ○ Hearing ○ Smell ○ Taste ○ Touch 4 Elementary Features of Stimuli: ○ Modality - major sensory modalities are mediated by distinct classes of receptor neurons...

Sensory coding and Somatosensation: 5 senses: ○ Vision ○ Hearing ○ Smell ○ Taste ○ Touch 4 Elementary Features of Stimuli: ○ Modality - major sensory modalities are mediated by distinct classes of receptor neurons located in specific sense organs; sensory receptors are specialized to transduce specific stimulus energy into electrical signals Chemoreceptor - smell, taste, pain Olfaction - sensory neurons in the olfactory epithelium are distributed in discrete zones ○ In situ hybridization to detect the expression of different odorant receptors ○ Each odorant receptor gene is expressed by a small subset of neurons within a single zone ○ Labels all neurons expression odorant receptors Photoreceptors - vision Individual photoreceptor is most responsive to light in particular spectral band; human perception of colors results from simultaneous activation of 3 different classes of photoreceptors in the retina Mechanoreceptors - touch, hearing, balance, proprioception Somatosensation - responds as long as pressure is applied to the skin; responds at the beginning and end of the stimulus ○ Responses of 2 different classes of touch receptors to a probe pressed into the skin Major sensory modalities are mediated by distinct neural circuits - specificity of each modality is maintained by the discrete anatomical pathways that terminate in unimodal nuclei in the CNS  ○ Location - location and spatial dimensions of a stimulus are conveyed through each receptor’s receptive field Receptive field in somatosensation - skin area/total domain in which stimuli can activate a sensory neuron ○ Intensity - firing rates of sensory neurons convey information about the stimulus intensity and time course Ex: somatosensation - as pressure increases, frequency of impulses increases (size and shape of impulse remains mostly the same) During steady pressure, firing rate is proportional to skin indentation - encode duration of stimulus ○ Neurons signal important properties of stimuli both when firing and not firing Receptor adaptation - when stimulus persists, the neural response diminishes (habituation) Rapidly adapting receptor - sense the rate at which stimuli is applied and removed ○ Duration -  ○ Sensory processing is modulated by different things at different levels: Attention, previous experience, psychological status, cultural differences, gender Sensation: ○ Somatic Sensation - pain, itch, temperature  Electrical stimulation of peripheral nerve at varying intensities activates different types of nerve fibers  Mechanoreceptors - mediate touch and proprioception (measure muscle activity and joint positions) ○ Muscle spindle is the principle receptor mediating proprioception Nociceptors - mediate pain and itch ○ Pain and touch are mediated by different neural circuits Somatosensory information enters CNS through cranial and spinal nerves ○ Dermatome - skin and deeper tissue innervated by a single spinal/cranial nerve ○ Distinct subsets of DRG sensory neurons project their central axons to different laminae in the spinal cord dorsal horn to constitute different neural circuits ○ Visceral Sensation - conscious and unconscious ○ Vestibular senses of balance ○ Neural Circuit: Sensory neuron -> brain stem -> thalamus -> primary somatosensory cortex -> primary motor cortex -> motor neuron -> muscle Touch and Pain: Pain and touch are mediated by different neural circuits  Mechanical stimulation @ receptor endings -> afferent pathways (mechanosensory fiber + pain and temperature fiber) -> cell bodies grouped into ganglia Tactile Pathway - primary somatic sensory cortex -> thalamus -> medulla (brain stem) -> up dorsal column (spinal cord)  4 Mechanoreceptors responsible for TOUCH: ○ RA1, SA1, RA2, SA2 (rapidly adapting - detect motion and vibration vs slowly adapting - detect object, pressure, form) ○ Type 1 - innervate superficial skin layer ○ Type 2 - innervate dermis and deeper skin layer ○ ○ Meissner Corpuscle - rapidly adapting in superficial skin (touch) ○ Merkel cells - slow adapting in superficial skin layer (touch) ○ Pacinian corpuscle - rapidly adapting in deeper skin layer (vibration/pressure) ○ Ruffini endings - slow adapting in deeper skin layer (stretch) ○ Receptor adaptation - when stimulus persists, the neural response diminishes  ○ Different types of mechanoreceptors act together to perceive the temporal/spatial patterns of stimulation When an object contacts the hand, displacement and indentation of the skin stretches the tissue and stimulate touch sensors ○ Mechanoreceptor Transduction Mechanical energy distorts channels -> opens pores Transduces energy -> electrical signal If receptor potential crosses threshold -> action potential ○ Different Fibers: Larger diameter = greater speed of AP Nociceptors ○ Pain receptors (nociceptors) sense chemical + thermal + mechanical stimuli ○ Pain Fibers:  Ao tingling/1st pain - first pain (sharp, transient) C fibers/2nd pain - second pain (dull + longer lasting) First identified thermal receptor - TRPV1 ○ TRP channels are major contributors to temperature, chemical, and pain sensation ○ Capsaicin - elicits sensation of burning pain ○ To identify capsaicin receptor - express sensory neuron genes in an in vitro cell line and examine their sensitivity to capsaicin HEK293 cell line (in vitro expression system) and calcium imaging to examine sensitivity to capsaicin Neuronal activation is frequently associated with increased Ca2+ Sensitization - tissue damage can cause peripheral + central sensitization ○ sensitization/hyperalgesia - normal touch can induce pain Nociceptors use glutamate + neuropeptides as NTs Neurogenic inflammation ○ Activation of nociceptors induces neurogenic inflammation Skin inflammation - redness and swelling Vasodilation - dilation of blood vessels -> redness (CGRP - neuropeptide) Plasma extravasation - fluid leakage out of capillaries -> swelling (substance P -> neuropeptide)  Neuropeptides can induce vasodilation and plasma extravasation; also activate immune cells to enhance inflammation and neuronal responses Peripheral Insults Induce sensitization of spinal neurons Peripheral exposure to NGF ○ NGF is upregulated in inflamed tissue ○ NGF-neutralizing molecules are effective analgesic ○ NGF enhance the excitability of nociceptors Retrograde transport of signaling endosomes - transportation of NGF to the nucleus Increased transcription of BDNF Central release of BDNF Pain Piezos and Itch: Descending control of pain ○ Pain is subjective - property of mind/brain ○ Pain perception depends on many factors - attention, expectation, gender, culture ○ Mechanical sensors close the gate in the pain circuit ○ OTC pain killers block production of prostaglandin (induces pain, fever, inflammation) to inhibit pain Prostaglandin sensitizes sensory nerves and induces hyperalgesia Tylenol, Aspirin, Ibuprofen all inhibit COX (enzymes that catalyzes synthesis of prostaglandin) ○ Lidocaine (local anesthetic) - blocker for voltage-gated Na+ channels Voltage Gated Na+ channels in sensory neurons: Nav1.7, Nav1.8, Nav1.9 are main Nav channels in sensory neurons -> target PNS specific molecules to avoid central side effects ○ Central Anaesthetic: Opioids Opiates interact with specific receptors in CNS Increase K+ conductance to hyperpolarize the membrane Inhibit Ca2+ channel to inhibit NT release  ○ Congenital Insensitivity to Pain: Inhibits ability to perceive physical pain Can tell difference between sharp vs dull, cold vs hot but cannot sense burning sensation Peripheral neuropathy Cause? SCN9A gene associated with coding or subunit of Na+ channel No channels - can’t transmit pain-inducing signal to brain Piezos: ○ Piezos = mechanotransduction channels Identified from RNAi screening in a mechanical sensitive mammalian cell line (Neuro2A cell line) Piezo1 is required for the mechanical sensitivity of Neuro2A cells Piezo1 is overexpressed in mechano-insensitive cells (HEK293T - cell line derived by human embryonic kidney cells grown in tissue culture) - piezo is sufficient to confer the mechanical sensitivity of cells Piezo2: ○ Inactivating variants in Piezo2 (loss of function) leads to: Selective loss of discriminative touch, perception, decreased proprioception, ataxia, and dysmetria Mechanically activated ion channels use stretch or pressure gating to open (ion channels)  RNA interference (RNAi) - RNA molecules inhibit gene expression or translation by neutralizing targeted mRNA molecules ○ Mechanotransduction channels in Merkel Cells Merkel cells transduce mechanical stimuli into electrical signals Piezo2 is a mechanical sensor in Merkel cells ○ Mechanotransduction channels in sensory neurons Piezo2 is a mechanical sensor in sensory neurons Piezo also mediates mechanical sensation in in vitro cultured cells and tissue ○ Itch:  ○ Antimalarial produces itch ○ Itch receptors Mrgprs (Mas-related G protein-coupled receptors) mediates non-histaminergic itch Mrgprs are expressed in small diameter neurons Deletion doesn’t affect acute pain sensation; blocks CQ-induced itch CQ directly activates DRG sensory neurons to induce itch -> response of DRG neurons to CQ is Mrgpr-dependent Might be a distinct itch neural pathway - GPRR is required for mediating itch sensation rather than pain ○ Neurodevelopment: Anencephaly - baby’s head isn’t fully developed during properly during pregnancy; brain started to develop correctly and then became damaged ○ Spinal bifida - incomplete closing of the backbone and membranes around the spinal cord Can cause mild to severe physical and intellectual disabilities Severity depends on size and location of opening in spine and if spinal cord and nerves are affected Development of the nervous system: ○ Underlies much of behavioral development - some behaviors cannot be displayed until nervous system can support ○ Environmental influences on development often based in nervous system change ○ Patterned by early developmental events - neural progenitor cells at different positions along the body axes produce different types of neurons Neuronal Birth +Migration - neurons are born when they exit the final cell cycle; post mitotic neurons migrate to target Axon Pathfinding - axons extend toward postsynaptic cells Dendrite Morphogenesis + Synapse Formation + Modification of Synaptic connections ○ General Features of Brain Development - 100-200 billion neurons, tons of synapses; simple units becoming increasingly complex Epigenesis - developmental course where things go from general to specific Starts off as ball of cells: Zygote - fertilized ova, cells dividing (cleavage) Morula - solid fall of ~100 cells blastula/blastocyst - solid ball forms fluid-filled center Gastrula - ball inverts upon self, forms layers ○ 3 layers: Endoderm - internal organs Mesoderm - skeleton, muscles, circulation system Ectoderm - skull, nervous system, skin   ○ Notochord induces cells of the ectoderm above it (the neural plate and neuroepithelium) to become primitive nervous system How does ectoderm know to become neural tissue? ○ Secreted signals promote neural cell fate ○ Organizer - specialized group of cells that control the differentiation of the neural plate from ectoderm ○ Transplantation - signals from the organizer region induce a second neural tube ○ Neural induction is mediated by peptide growth factors and their inhibitors BMP (bone morphogenetic protein) signals from the organizer region spread through the ectoderm to induce neural tissue BMP inhibitors secreted from the organizer region bind to BMPs block ectodermal cells from becoming epidermal; promote neural tissue formation ○ Neural Inducers: Proteins like noggin and chordin induce neural tissue development  UV treated embryos implanted with cDNA from the organizer region of normal embryo or Li-treated embryo rescues UV Inducers inhibit BMP ○ Neural Induction is mediated by peptide growth factors and their inhibitors Extrinsic factors - inductive factors secreted by the neighboring cells and organization centers Some factors generate a signaling gradient that can span the entire neural tube, others act more locally Intrinsic factors - distinct transcription profile that allows the cells to respond to inductive signals Neurulation starts around day 21, ends by day 28 Nervous system is highly patterned as a consequence of early developmental events Neural tube becomes regionalized early in embryogenesis ○ 3-vesicle stage -> 5 vesicle stage ○ Functional domains are the products of progressive patterning and subdivision of the neural tube ○ Rostrocaudal pattern of the neural plate Morphogen - signal that can direct patterning and different cell fates at different concentration thresholds (BMP, Wnt, Shh, Ephrin) Wnt and Wnt inhibitors - secreted by mesodermal and endodermal cells around neural plate ○ Cells in anterior and posterior regions of the neural plate express different transcription factors ○ Developmental events regulated by a variety of secreted signals Anencephaly - upper part of the neural tube doesn’t close all the way  Neurodevelopment continued: Basic processes for building a brain: ○ 1) Cell birth - from inside surface of neural tube; ventricular zone gives rise to new cells (neuroepithelial cells - neural stem cells) Can see this through thymidine and BrDU; new DNA needs thymidine (a nucleoside, precursor to thymine); BrDU similar to thymidine, and tricks cells  If inject on any day, some new cells have BrDU in them instead of thymidine; can later look for cells with BrDU; euthanize earlier, see cells’ origin; euthanize later, see cells’ final place Radial glial cells serve as neural progenitors and structure scaffolds RGC - radial glial cells (neural progenitors); RGC nuclei migrate along the apical-based axis as they progress through cell cycle RGC go through cell cycle and mitosis to generate neurons and glia Post mitotic neurons - newborn neurons that do not go through cell cycle Newly generated cells migrate away from ventricular zone using RGCs as a guide ○ 2) cell migration Newly generated cells migrate away from ventricular zone using RGCs as a guide Central neurons migrate along glial cells and axons to reach their final target ○ 3) differentiation Cells become specialized Over 200 types of neurons (morphology, receptors, NTs) Determined genetically and local molecules Targets determine NT phenotype of a neuron Excitatory and inhibitory neurons are derived from different proliferative zones; NT phenotype of a CNS neuron is controlled by a transcription factors; NT phenotype of a peripheral neuron is influenced by signals from target Survival of a neuron is regulated by neurotrophic signals from the neuron’s target; survival of motor neurons depends on signals provided by their muscle targets Neurotrophic factors secreted by target cells are critical for neural survival Neurotrophic factor hypothesis: cells at or near target of neuron secrete small amounts of an essential nutrient or trophic factor  Neurotrophins - family of proteins important for the survival, development, and function of neurons ○ Secreted proteins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4 ○ binds to specific receptors; transported to cell body to promote neuronal survival via retrograde signaling ○ Different neurotrophic factors promote survival of distinct populations of neurons and induce intracellular signaling pathway low/no neurotrophic factors: neurons die via apoptosis Cells express a conserved death program ○ Apoptosis - programmed cell death, highly regulated and controlled, happens throughout an organism’s life cycle Apoptosis is affected by perinatal/postnatal experiences; measure markers of apoptosis ○ Necrosis - traumatic cell death results from acute cellular injury ○ Death signal - cell stress such as DNA damage and anoxia Neurotrophic factors suppress caspase activation and cell death ○ Ligand-activated death receptors ○ Stress-induced signals, like DNA damage, activate mitochondrial proteins ○ 4) axon outgrowth and synapse formation Differences in the molecular properties of axons and dendrites emerge early in development Neuronal polarity - distinction between axons and dendrites; established through rearrangements of cytoskeleton ○ Axon marker: Tau (dephosphorylated) ○ 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 the neuronal morphology Dendrite morphologies in tissue culture look like those in vivo, indicating critical role of intrinsic factors Extrinsic factors: secreted by cells near pial surface, laminin promote axon generation in ECM, semaphorin promotes dendrite formation; orientation neurons disrupted in semaphorin-3A mutant 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, absent from dendritic spines axon terminals F-actins - direct local traffic, accumulate in axon terminals and spines Growth cone - specialized structure at tip of axon  ○ Express receptors to sense guidance cues ○ Responsible for axonal elongation and pathfinding Axons guided by chemical gradients of attractants and repellents Chemicals made by glia Diverse signaling control growth and guidance of developing axons ○ Cell adhesion molecules: help cells stick ○ chemoattractive/chemorepulsive cues ○ Some morphogens such as BMPs, Wnts, Shhs, FGFs ○ Changes in intracellular signaling can determine if the same cue attracts or repels ○ PKA activity and intracellular cAMP levels are low = repellant ○ PKA activity and intracellular cAMP levels are high = attractant ○ 5) synaptic pruning Most synapses made by 2 years old Regression during next 3 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 mean by which activity can refine specific synaptic connections Competitive synapse elimination shapes the connectivity Sensory inputs are critical for neurodevelopment Broad tissue arbors become denser and focused Molecular cues control initial specificity but since circuit begins to function, specificity is sharpened through neural activity  Genetically determined connectivity followed by experience-dependent reorganization Axons make choices among potential postsynaptic partners to form synaptic connections Cell-cell contact differentiate into specialized pre- and postsynaptic terminals Synapses undergo major rearrangements to mature (synaptic elimination and synaptic strengthening) Central synapses develop rapidly via clustering proteins NT receptors become localized at central synapses Scaffold proteins cluster NT receptors at synapses; different mechanisms exist to organize different types of synapses Synaptic organizing molecules pattern central synapses ○ Neurologin-neurexin complexes link pre- and postsynaptic membranes at central synapses ○ ○ Recognition of synaptic targets in specific Specificity of synaptic connections is particularly evident when intertwined axons select subsets of target cells Axons arise from specific parts of spinal cord to targets Reestablishment of selectivity in adults after nerve damage Specificity doesn’t emerge through embryonic timing or neuronal positioning Subcellular site selection of synaptogenesis uses both attractive and repulsive mechanisms Subcellular distribution of neurofascin directs basket cell presynaptic terminal formation NF: neurofascin, an Ig superfamily molecule, cue for synapse formation ankyrinG: intracellular scaffolding protein, organize neurofascin distribution, highly concentrated at the axon initial segment  Synapses are strategically placed at specified locations in postsynaptic neurons Neuropsychiatric Diseases: Depression - persistently depressed mood/loss of interest in activities, causing significant impairment in daily life ○ Associated with hypofrontality ○ Chronic stress can impair frontal cortex function contributing to depression ○ Stress signaling pathways that impair prefrontal cortex structure and function ○ 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 the anhedonia symptom of depression GC-induced loss of prefrontal dendritic spines is associated with depression-like behavior ○ Elevated GC for 20 days (compared to control and a washout period of 1 week) Quantified: dendritic spines in the frontal cortex, sucrose consumption Heterozygosity of cytoskeletal supporting genes impairs resilience to (subthreshold) elevation of GCs ○ Heterozygous - loss of one gene copy ○ Subthreshold B - dosing that doesn’t cause behavioral defits in healthy animals In depression, serotonergic innervation from the raphe nucleus is often reduced Serotonin hypothesis of depression: Diminished activity of serotonin pathways possible mechanism in the pathophysiology of depression Amine-depleting drugs, such as reserpine, cause depression-like behaviors Drugs that alleviate depression typically potentiate the effects of serotonin at the synapse Genetic and imagine evidence that serotonin siglaing is involved in depression Actions of antidepressant drugs at serotonergic SSRI treatment  Although neurochemically, drugs have effects on increasing synaptic serotonin rapidly Takes 4-6 weeks for effects on mood May be due to slow neural remodeling or new proteins, neurogenesis