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What is neuroscience?
Neuroscience is a field of scientific study that seeks to understand how the nervous system carries out its functions and what goes wrong when it doesn’t.
While humankind has learned alot about nervous system structure and function, there is a great deal left to understand. It's up to you to figure it all out.
http://courses.pbsci.ucsc.edu/mcdb/bio125/
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Welcome. This class will be an Introduction to Neuroscience– Neuroscience is a field that by necessity integrates information and techniques from many other scientific disciplines— not just biological sciences like genetics, molecular biology, biochemistry, immunology, physiology. But also physics, engineering, computer science, psychology. And these days neuroscience is touching upon fields as varied as sociology, criminology, marketing, ethics, and the law. So what is Neuroscience? Neuroscience is fundamentally a field that...
And ultimately it is a field of science that seeks to understand how this lump of biological tissue siting inside our heads has evolved the capability of asking questions about its own nature and existence.
Thus it will be you, and your children, and your children’s children that will figure it all out and literally allow human beings to reach the stars.
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What are the nervous system’s functions?
- The nervous system organizes and controls an individual’s appropriate interactions with the environment
- Thus, it’s functions are dynamic, vast and wide-ranging – extending to include all thoughts, perceptions, bodily actions, behaviors, and even the very essence of one’s being: consciousness and the mind
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What does the nervous system do? It organizes and controls an individuals interactions with the environment. It does this by processing current or past experiential information and making and executing behavioral decisions.
Therefore the brain’s functions are dynamic, vast and wide ranging, and extends to include all thoughts, perceptions, and actions and the very core of what it means for each of one us to be us–– consciousness and the mind. It is this complex lump of biological tissue, this emergent computational system that allows us humans to not only imagine the future, but to create it as well.
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Neuroscience and the future of humankind
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Ever since the dawn of the industrial age in the mid 19th century and Jules Verne's 1865 novel 'From the Earth to the Moon' humans have been dreaming of the future, not just here but among the stars. And those futures can become reality like when the Apollo astronauts landed on the moon and acknowledged the inspiration that Verne's orig sci-fi novel had on many.
Neuroscience and its role for proper physiological function is going to play a role in many advances in health and technology for humankind now and far into the future--
To reach the stars we will need:
- robots, artificial intelligence, I. Asimov Philip K. Dick's 1968 novel 'Do Androids Dream of Electric Sheep'
- virtual reality, brain machine interfaces, James Cameron's Avatar
- medical tricorders, 1960s series Star Trek
- physiological stasis, cryopreservation, waking up the brain space after travel like Joe Haldeman's 1974 novel 'The Forever War' or the Ridley Scott's movie Aliens
The human brain and its limitless creativity has packed a bunch of computational power into this little device in our pocket. And yet this device is really just made up of lots of simple little semiconductive elements. The human brain even invented this masking tape that currently holds together my broken phone. So what is the atomic unit of our brains function and how is it structured to achieve our cognitive abilities and our consciousness? We will find the answers to some of these question in this course, but will also discover as is usually the case when looking into nature's secrets that we humbly know so little.
Or futures that seem impossibly fanciful but who knows 10k or 100k years, maybe consciousness will be woven into some sort of singular virtual world like in the matrix or the cylons from Battle Star Galactica.
think of virtual reality which is now almost a reality, can we solve the mismatches between sensory information and body positioning to get rid of the nausea associated with this technology? Think of artifical intelligence and robotics
If we will be traveling through space we will need to keep our bodies disease free to get wherever we are going-- will be know enough about brain function and neurolgical disease to fix things on the fly with a medical tricorder device like in Star Trek?
Can we read the minds of a suspect in a courtroom with a brain imaging device? Do we even want to do that? Think of Can we rid
The human brain and its limitless creativity has packed a bunch of computational power into this little device in our pocket. And yet this device is really just made up of lots of simple little semiconductive elements. The human brain even invented this masking tape that currently holds together my broken phone. So what is the atomic unit of our brains function and how is it assembled to achieve our cognitive abilities? We will find the answers to some of these question in this course, but will also discover as is usually the case when looking into nature's secrets that we know so little.
Since that time we've dreamed up fantastical futures in shows like Star Trek and the Jetsons and dystopian ones in Blade Runner and the Terminator or even ones past (for example think "long time ago in a galaxy far far away...")
Many of things dreamed of are already presentImagine some of things thought of and now already present flying aeroplanes, personal landspeeders, rocket ships to distant planets \
- Edgar Rice Burroughs John Carter thought waves example.
Penfield mood organ
We will focus on a few basic features of the nervous system
- The mechanisms by which neurons produce signals
- The patterns of connections between nerve cells
- The relationship of different patterns of interconnections to different types of behavior
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- Nervous
- relating to or affecting the nerves
- nervosus
- latin
- sinewy, vigorous
- nervus
- latin
- sinew
- sinew
- fibrous tissue linking bone or muscle to bone
- the parts of a structure, system, or thing that give it strength or bind it together
The nervous system and its function is the product of both our genes and our environment
- We are now in a gene-centric “post-genomic” phase of neuroscience
- Human genome sequenced- approximately 20,000 genes.
- Most genes are expressed in the brain, either during development or in the adult. It is the spatial and temporal regulation of these genes that builds a nervous system.
- Mice, flies, and worms have nervous systems and even express many of the same genes as humans. Genetics allows us to correlate gene activity with nervous system function.
- Neuroscience therefore encompasses many fields, including genetics, cell biology, physiology, and development biology.
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Genome size does not predict nervous system complexity
| organism | # of genes | # of base pairs | # of neurons | development time (young adult) |
|---|---|---|---|---|
| Caenorhabditis elegans (nematode) | ~19,000 | ~97 million | 302 | 8 hrs |
| Drosophila melanogaster (fruit fly) | ~15,000 | ~120 million | ~250,000 | 7–11 days |
| Danio rerio (zebrafish) | ~24,000 | ~1.5 billion | ~10,000,000 | 30 days |
| Mouse | ~25,000 | ~3.5 billion | ~71,000,000 | 2-3 months |
| Human | ~20,000 | ~3.5 billion | ~100,000,000,000 | 18 years |
| African elephant | ~20,000 | ~3.1 billion | ~267,000,000,000 | 18 years |
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Number of genes is not related to nervous system complexity or size. The nematode c. elegans has just 302 neurons, and yet its genome contains virtually as many genes as a humans. An african elephant brain weighs 3 times more than a human brain and has 3 times the number of neurons.
The largest brains are those of sperm whales, weighing about 8 kg (18 lb). An elephant's brain weighs just over 5 kg (11 lb), a bottlenose dolphin's 1.5 to 1.7 kg (3.3 to 3.7 lb), whereas a human brain is around 1.3 to 1.5 kg (2.9 to 3.3 lb). Brain size tends to vary according to body size.
- Drosophila 7-11 days (28-34degs C)
- zebrafish 3-4 days juvenile swimming and visual behavior. young adult at 3 mo. full adult at 6 mo.
- genome sizes at http://www.biology-pages.info/G/GenomeSizes.html
There are many brain-specific and non-brain specific genes expressed in the nervous system
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Out of those 20000 genes, there are many expressed genes that are common between the nervous system and other tissues, however there is also a substantial fraction that are expressed specifically in the nervous system
A single mutation can lead to dramatic brain size defects
Mutation in a spindle pole gene call ASPM1
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Now mutations in single genes in the right place in our genome can cause drastic effects on the formation of our brain’s wiring.
For example, shown here is a person with a mutation in ASPM1 a protein used to make spindle poles for mitotic stem cells during embryonic development.
But most single gene mutations do not cause such drastic effects, with a more subtle and complex set of genetic and environmental risk factors causing neurological disease, similar to and probably exceeding the complex etiology of cancer.
Model organisms— C. elegans
- It is hard to visualize and monitor neurons and manipulate genes in humans so neuroscientists study a number of different organisms
- The nematode worm C. elegans is great for genetic engineering and has a tiny nervous system (just 302 neurons)
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Now to do neuroscience research we have to use model organisms of course. Small number of neurons, can be labeled using green fluorescent protein or other means.
C. elegans is a nematode or roundworm. It is non-infectious and non-parasitic organism just 1 mm long and it can be easily genetically engineered. That means you can introduce mutations to genes or express fancy inert proteins that allow you to track the function of genes and cells in living animals making it a great model organism. For neuroscientists it has only 302 total neurons making it a great model organism. Many mutant worms have been isolated that affect nervous system function allowing us to learn about the function of those genes. And you can engineer the worms to express fluorescent proteins so that the animal's neurons glow under a microscope. How many of you have heard of green fluorescent protein?
However, we have more than a million neurons that just form the optic nerve from each of our eyes!
Model organisms— squid
Squids have unusually large axons (1 mm diameter)
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Jules Verne provided inspiration for the space age
Phylum: Mollusca Class: Cephalopoda Order: Teuthida Family: Loliginidae Genus: Loligo
Atlantic squid (Loligo pealei)
Phylum: Mollusca Class: Cephalopoda Order: Sepiida Family: Sepiidae Genus: Sepia
Squids are arguably the most important model organism in the history of neuroscience. They are rarely studied anymore but their large axons which are 1mm in diameter-- 1000x bigger than our axons-- made their axons amenable to sticking electrodes inside them in the 1930s-50s and allowed neuroscientist to discover the biophysical and mathematical basis of neuronal signaling. We will discuss squid giant axons in much more detail soon.
Other important invertebrate organisms in neuroscience research include sea slugs and fruit flies and zebrafish. Some of these are very amenable to genetic engineering like C. elegans and have nervous systems more similar to our own.
Model organisms— Mus. musculus
The mouse is a common model in neuroscience research.
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But mammals are the only animals that have evolved a convoluted superficial part of the brain called the neocortex. And it is the cerebral neocortex is crucial for our highest cognitive functions, even if it sometimes seems that in election years that humans have lost their cerebral function.
Thus for research pertaining to the structure and function of the mammalian brain and human disease we turn to rodents like the common house mouse. Mice are small with a brain 2 cm in length, develop fairly quickly, and their genome has long been one of the most amenable to genetic engineering though this is quickly changing newer molecular biology techniques (like the CRISPR/Cas9 system).
- Mouse brain is about 2 cm in length
- genetically tractable
- https://www.youtube.com/watch?v=stPThgZ2Y5o
Model organisms– other mammals
Higher mammals are used to study more complex brain functions.
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Research with cats was critical for work from the 1950s to 1980s that allowed neuroscientist to learn how visual signals are processed in the highest circuits of the mammalian brain.
And research with rhesus monkeys has been essential for learning about perceptual, attentional, and decision making in the mammalian brain together with research into brain-machine interfaces that have direct clinical applications for human patients.
3rs: Replacement, Reduction, and Refinement
Brain lesion patients
- Lesions in brains or degenerative diseases help us understand brain function
- Phineas Gage– Railroad spike through frontal lobes changed his personality
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Furthermore, studies of patients with brain lesions has historically been key to localizing parts of the brain that affect emotional states and learning and memory.
e.g. Phineas Gage in 1848 his whole personality changed after the spike went through his brain.
Harlow wrote: "the equilibrium... between his intellectual faculties and his animal propensities seems to have been destroyed"
What are brains made of?
A glob of squishy jello?
Cells.
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So what are brains made of? Anybody? Jello? What is this 1.5 kg or 3 lb human brain made of?
Yes it is soft and squishy but it is not just a gelanitous mass like jello. Shown here is a section through a human brain. It is about 20 cm long and if we were to zoom in on a tiny part of it and use a special dye and microscope what we see is that the brain is made of cells. So this is a pyramidal neuron in from the cerebral cortex and its cell body is about 30-40µm in diameter.
Brains are made of cells
- Camillo Golgi (Italy)– believed that cells in the brain were directly connected forming a continuous network (reticular theory).
- Santiago Ramon y Cajal (Spain)– Brains made up of single cells and communicate at specialized areas called synapses.
- Shared Nobel prize in 1906
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Seems fairly obvious now. But wasn't in the 19th c. Cells widely accepted everywhere else in the 1830’s. But neuroscientists were the last to accept this right up until the turn of the 20th c.
Only after fundamental and rigorous work by these two scientists, C. Golgi and S. Ramon y Cajal in the late 19th c. did we come to appreciate comprised of individual cellular elements rather than a
Golgi staining
Golgi staining: potassium chromate and silver nitrate (1873)
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Golgi's drawing of hippocampus after performing his black potassum chromate and silver nitrate stain. Bottom is a zoomed in drawing of neurons and their connections in the hippocampal dentage gyrus.
The nervous system is not a syncytium
- syncytium: a mass of cytoplasm with many nuclei but no internal cell boundries
- reticulum: a fine network or netlike structure
- Camillo Golgi, Nobel Lecture December 11, 1906, The Neuron Doctrine- theory and facts:
"...Far from being able to accept the idea of the individuality and independence of each nerve element, I have never had reason, up to now, to give up the concept which I have always stressed, that nerve cells, instead of working individually, act together, so that we must think that several groups of elements exercise a cumulative effect on the peripheral organs through whole bundles of fibers."
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Golgi drew the structure of the hippocampus as being all fused together into a reticulum, no free axon endings
The Neuron Doctrine
- Santiago Ramon y Cajal
- Neurons are cells. Each is an individual entity anatomically, embryologically, and functionally.
- Neurons have a functional polarity
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Neurons in culture have specific endings. EM methods, dye filling experiments.
Heinrich Wilhelm Gottfried von Waldeyer-Hartz (6 October 1836 – 23 January 1921) was a German anatomist and conceived the word 'neuron'.
Golgi in his nobel lecture:
(3) The neuron is a physiological unit. This fundamental idea which Waldeyer expressed with perfect precision has been enlarged upon both from anatomical and functional sides with additional propositions, for example : The communication between neurons is only established by casual contact. There is scarcely any nervous tissue apart from the neurons; the neurons are also trophic units.
The Nobel Prize in Physiology or Medicine 1906
"in recognition of their work on the structure of the nervous system"
Camillo Golgi
Pavia University
Pavia, Italy
Santiago Ramón y Cajal
Madrid University
Madrid, Spain
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How many neurons in a human brain?
- 100 thousand
- 10 million
- 100 million
- 1 billion
- 10 billion
- 100 billion
- 1 trillion
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- in cerebral cortex humans generally have most neurons, where we have about 20 billion. Even compared to an elephant that has 3 times the number of overall neurons. Though some species of cetaceans (whales and dolphins) approach the number of our cortical neurons and recent research has shown that the long-finned pilot whale likely has more neurons in its cerebral cortex than we do.
Glial cells
- Glia
- greek for 'glue'
- outnumber neurons 10-50 fold
- structural support for neurons
- remove debris and maintain a functional nervous system environment
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Now there are two basic cell types in the nervous system, neurons and glia. We will revisit neurons more in a few minutes and will be talking all about their function over the ensuing lectures but first lets touch briefly on some of the types of glial cells and their known functions.
Types of glia
- Astrocytes– Support cells of the CNS, most numerous type of glia
- Microglia- CNS macrophages. Act as phagocytes, mobilized after infection, injury, or disease
- Oligodendrocytes– Myelin producing cells of the CNS
- Schwann cells– Myelin producing cells of the PNS
- Satellite cells– Support cells of the PNS
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Satellite glial cells are glial cells that cover the surface of nerve cell bodies in sensory, sympathetic and parasympathetic ganglia.
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Astrocytes
- Restricted to CNS
- Maintain a proper chemical environment
- Deliver metabolic support to neurons from blood vessels
- Help maintain the blood-brain barrier
- Neurochemical recycling at synapses
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Astrocytes are star shaped, hence their name.
Astrocytes are your pizza delivery persons for neurons. They are also like your mom, constantly upkeeping your room or synapses as is the case for neurons.
They are the direct decendents of the mother stem cells that give rise to the neurons and glia of the nervous system.
Devasting diseases of astrocyte function include brain cancer with gliomas like glioblastomas typicaly being comprised of astrocytes gone wild. It is also thought that some childhoold epilepsies may originate from altered astrocyte function.
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Oligodendrocytes
- Insulate axons in CNS by wrapping in myelin sheaths. Myelination is essential for electrical signal propagation
- Each cell can myelinate multiple axons
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Multiple sclerosis or MS is an example of a devastating CNS disease characterized by degeneration of the myelin sheaths.
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Schwann cells
- Myelinate axons in peripheral nervous system (PNS)
- One axon per cell
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Discovered by German scientist Theodore Schwann. In 1839 he actually stated that all animal tissues are made of cells.
A number of other demylinating diseases other than MS that involve schwann cell dysfunction. Charcot–Marie–Tooth disease (CMT), Guillain–Barré syndrome.
Neurons
- Main signaling unit of the nervous system
- Polarized– have dendrites and axons and a direction for information flow
- Communicate by electricity– usually using action potentials.
- Tremendous range of different cell types– categorized by morphology, molecular identity and physiological activity.
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Now let’s think about the cell type most responsible for the brain’s business of biological computation— the neuron.
It is the...
Which of the following cell structures are found in neurons?
- DNA
- RNA
- Nucleus
- ER
- Mitochondria
- Microtubules
- Golgi
- Cell division machinery
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Cell body (soma) of a neuron
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- soma is another word for cell body
- the processes extending away from the cell body, the dendrites and axons are filled with cytoskeletal support like microtubles and actin filaments. Provide shape and structure to the neuron and are important during development of processes. Neurodegenerative diseases like alzheimers often affect components of the cytoskeleton (microtubles or actin filaments)
Neurons have a functional polarity
- Incoming information arrives and is integrated among the dendrites and cell body
- The integrated information is then relayed along the axon to the next neuron via synapses
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Structures of a neuron
- cell body (soma)– metabolic center of the cell, contains the nucleus.
- dendrites– receive incoming signals from other nerve cells
- axon– carries signals to other neurons
- axon hillock– initiates action potentials
- synapse– site at which two neurons communicate
- synaptic cleft– area between pre and post-synaptic cell
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Neuron processes: dendrites
- Dendrites
- Extensively branching from the cell body
- Transmit electrical signals (graded potentials) toward the cell body
- Function as receptive sites for other neurons
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Dendritic spines
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- 2 billion transistors in an iphone6.
- 100 billion neurons, each receiving up to 10000 synaptic connections
- quadrillion synapses, 10^15 in our nervous system
False color of the dendrite of one neuron near an axon from another neuron from an EM image
- semiconductors 22nm to 14nm (half distance between nodes on the array)
- synaptic vesicles, avg diameter of 40nm 1
- diameter of neurofilament 10nm 1
- thickness of neuronal membrane 5 nm 1
- synaptic cleft distance 20-40nm 1
- internodal length 150-1500µm 1
- dendritic spine membrane area in rat striatum-- 0.5µm^2 == 0.4µm radius == 0.8µm diameter 2
- neck diameter 0.15µm 2
- spine density 40 spines/10nm 2
Neuron processes: axons
- Axons (nerve fibers)
- Each neuron has only one, but it can branch
- Neurofilaments, actin microfilaments, and microtubules
- Provide structural strength along length of axon
- Axonal transport of biochemical substances
- Carry neuronal electrial signals (action potentials) away from the cell body
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?chalkboard
- Branches along length are infrequent. End is called terminal bouton or axonal arbors
- Aid in the transport of substances to and from the cell body
- Impulse generator and conductor
- Axon collaterals
- Multiple branches at end of axon
- Terminal branches
- End in knobs called axon terminals (also called end bulbs or boutons)
Neuron signals: action potentials
- Nerve impulse (action potential or 'spike')
- Neuron receives and sends signals
- Generated at the initial segment of the axon
- Conducted along the axon
- Releases neurotransmitters at axon terminals
- Neurotransmitters – excite or inhibit neurons
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We will be discussing the nature of basic unit of nervous conduction, the action potential or impulse in great detail in ensuing lectures.
Neurons are classified in different ways
- Morphology: unipolar, bipolar, and multipolar
- Function: sensory neurons, motor neurons, and interneurons
- Neurotransmitter expression: excitatory, inhibitory, dopaminergic, etc.
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- similar classes of cells and morphologies and neuronal shapes found in the human nervous system as in other animals. People have looked hard but there doesn't appear to be any class of cell that is unique to humans or higher mammals-- i.e. no unique neuron subtype that makes us human. We'll talk alot about the neurochemical differences that underly different types of neurons later in the course and their different functional properties.
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Example morphologies– cerebellar neurons
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Example morphologies– cortical neurons
- Pyramidal neurons– multipolar neurons that contain both apical and basal dendrite. Also contain one axon.
- Most common excitatory neuron in the cerebral cortex
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Example morphologies– retinal neurons
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?Grab Coombs et al., 2006 figures...
Structure of a sensory neuron (afferent)
Function of an afferent neuron is to carry information from the sensory periphery towards the CNS or brain.
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Afferent- term meaning to send information from periphery to the CNS or to brain
Structure of a motor neuron (efferent)
Function of an efferent neuron is to carry information towards the muscles for effecting behavior.
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Efferent sends info to muscles
Affect vs effect
Neurons communicate by electricity
- Axons project great distances
- Use action potentials to transmit information
- Neuronal interactions ('functional connections') occur at synapses
- separated by small amounts of space– the synaptic cleft (~40 nm)
- Action potential causes release of neurotransmitter that is received by post-synaptic cells
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Inter-neuronal signaling occurs at synapses
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We will be going into synapse structure and function in much detail later in the class, but just to complete our introduction to basic anatomical details of neurons this figure illustrates...
Properties of the action potential
- rapid
- transient
- all or none
- self-regenerating
- can go long distances. 5 m in a giraffe
- highly stereotyped
- discrimination is based on patterns of firing
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15 m if you're a branchiosaurus
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rate coding
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phase coding
Neural Circuits
- Neurons don’t function in isolation, they are organized into circuits that process specific kinds of information
- Direction of information flow is important for understanding the function of a circuit
- Afferent neurons– carry information toward the brain
- Efferent– carry info from the brain
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Example of a simple circuit: stretch reflex (myotatic reflex)
The "knee-jerk response" is a simple reflex circuit.
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Muscle lengthens, stretching muscle spindle (sensory ending), leading to incr alpha motor neuron activity and causing same muscle group to contract. Works to maintain muscle length.
- stretch tendon and sensory recpetors in leg extensor muscle
- sensory neuron synapse with and excites motor neuron in spinal cord
- sensory neuron also excites spinal interneuron
- interneuron synapse inhibits motor neuron to flexor muscles
- motor neuron cducts APs to synapse on extensor muscle fibers causing contraction
- flexor muscle relaxes because its motor neurons activity has been reduced
- leg extends
Ways to measure neural activity
- Extracellular recording– an electrode is placed near a neuron. Measures action potentials. Useful for detecting patterns of activity.
- Intracellular recording– an electrode is placed inside a neuron-can measure smaller graded potential changes. Useful for isolating responses to single inputs.
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You might have the anatomy skills of Cajal or Golgi and you know there is this reflex you're studying and you've seen the morphologies of hundreds of cells along this pathway, but what is the cells function during this behavior, how do you monitor that?
Extracellularly recorded responses underlying the myotatic reflex
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These ticks are spikes or action potentials recorded extracelluarly. Since the electrode tip is placed close to the neurons cell membrane, the electrode can pick up signals as they pass by. A little bit like someone wiretapping your phone line.
Intracellularly recorded reponses underlying the myotatic reflex
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We will come back to this reflex circuit in greater detail time and again as we go through this course.
And really, the basic logic of this circuit and variants of it is replicated all over the brain and teasing apart all the types of cells, their response properties, and their functional interactions or connections with one another for all types of different sensory and motor behavior is the grand challenge, beauty, and fun of modern and future neuroscience.