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</div>
<!-- <figure><figcaption class="big">Types of somatosensory afferents linking receptors to the CNS</figcaption><img src="figs/Neuroscience5e-Tab-09.01_copy_653cef2.jpg" height="400px"><figcaption>Neuroscience 5e Table 01</figcaption></figure> -->
<!--
<figure><figcaption class="big">Types of somatosensory afferents linking receptors to the CNS</figcaption><img src="figs/Neuroscience5e-Tab-09.01_copy_653cef2.jpg" height="400px"><figcaption>Neuroscience 5e Table 01</figcaption></figure>
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## Activity patterns in different mechanosensory afferents as Braille is read
<figure><img src="figs/Neuroscience5e-Fig-09.06-0_aaf10ad.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 9.6</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-09.06-0_aaf10ad.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 9.6</figcaption></figure>
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## Pain perception is subjective
* Rubbing the site of injury can make pain less severe
* Pain is somewhat subjective. Depends on context. Soldiers wounded in battle feel less pain than if one gets the same injury at home
* Rubbing the site of injury can make pain less severe. Soldiers wounded in battle feel less pain than if one gets the same injury at home
* Pain can be subjective. Depends on context.
* There is a descending pain pathway that can impinge on the dorsal horn to quiet neurons
Note:
@@ -1017,9 +1019,6 @@ Note:
## Modulation of ascending pain signal transmission
1. Axons from neurons with mechanoreceptors can synapse onto inhibitory interneurons in spine to dampen pain response
2. Descending pathways from the brainstem can dampen pain response
<div><img src="figs/Neuroscience5e-Fig-10.08-1R_09cfa4c.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 10.8</figcaption></div>
@@ -1027,7 +1026,7 @@ Note:
enkephalins, endorphins, dynorphins— present in the periacq. gray matter, ventral medulla, and in spinal cord regions in dorsal horn.
Also CB1 and endocannabinoids work similiarly here in the dorsal horn.
Also CB1 and endocannabinoids work similiarly here in the dorsal horn. CB1 on presynaptic terminals of dorsal horn nociceptive terminals can be activated by endocannabinoid release in a retrograde fashion and decrease the release of neurotransmitters such as GABA and glutamate. *Interestingly, the analgesic effecs of PAG stimulation is blocked if CB1 antagonists are administered* highlighting the importance of endocannabinoids in descending control of pain transmission.
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## Brain damage and visual perception
<div><img src="figs/ScreenShot2015-09-11at5.11.54PM_241cf9a.png" height="400px"><figcaption></figcaption></div>
<div><img src="figs/2015-09-1116.47.12_3eb196a.png" height="400px"><figcaption></figcaption></div>
Note:
Let’s begin by going discussing one of the fantastic true stories told by the famous NYC neurologist, Oliver Sacks, who passed away just a few months ago and who weaved engaging clinical accounts and wrote a number of best selling books regarding cases of patients having extraordinary behaviors that resulted from strange or unknown neurological disorders including this one called The Man Who Mistook his Wife for a Hat. —>Indeed one of these accounts was about a man who actually mistook his wife’s face for a hat. This man, who was an accomplished musician and teacher at a school of music had developed trouble seeing faces and recognizing many types of objects in general as a result of degeneration in the visual system, likely from a stroke or something.
…these types of stories summarize a large bit of what neuroscience is about— understanding fundamental circuits that comprise brain function and animal behavior as well as the dually fascinating and devastating consequences that occur when the formation of those fundamental circuits goes awry.
---
## Brain damage and visual perception
<div style="font-size:0.8em;">
<div></div>
* The patient (‘Dr. P’):
* good visual acuity & color vision
* good recognition of abstract geometric objects (cubes, spheres, etc)
* Trouble recognizing friends, family, pupils
* Trouble recognizing complex objects
* Describing a rose: “About six inches in length. A convoluted red form with a linear green attachment”
* Describing a glove: “A continuous surface, infolded on itself. It appears to have five outpouchings”
</div>
👵🏻
🎩
Note:
Let’s begin by going discussing one of the fantastic true stories told by the famous NYC neurologist, Oliver Sacks, who passed away just last summer and who weaved engaging clinical accounts and wrote a number of best selling books regarding cases of patients having extraordinary behaviors that resulted from strange or unknown neurological disorders including this one called The Man Who Mistook his Wife for a Hat. —>Indeed one of these accounts was about a man who actually mistook his wife’s face for a hat. This man, who was a well regarded and accomplished musician and teacher at a NY school of music had developed trouble seeing faces and recognizing many types of objects in general as a result of degeneration in the visual system, likely from a stroke.
This patient (let’s call him Dr. P)… was cognitively sharp, had good vis…
Hard time...
visual agnosia, prospognosia, lesion somewhere in temporal lobe of the cerebral cortex for reasons we will hopefully discover partially by the end of today’s class.
For him the visual world was a series of lifeless abstractions, seeing and describing the world almost the way a machine would see it without grasping the big picture.
…these types of stories summarize a large bit of what neuroscience is about— understanding fundamental circuits that comprise brain function and animal behavior as well as the dually fascinating and devastating consequences that occur when the formation of those fundamental circuits goes awry.
---
## The visual pathway– retinotopy
Hubel, 1988
retina
superior colliculus,
dLGN,
visual cortex
<div><img src="figs/droppedImage1_951ed66.pdf" height="100px"><figcaption></figcaption></div>
<div><img src="figs/retinotopic_mapping_80f68b4.jpg" height="100px"><figcaption></figcaption></div>
Note:
Neighboring retinal ganglion cells in the eye detect changes in contrast from similar portions of the visual field, thus forming a 2D map of visual space in the retina. This spatial representation of objects in the retina is then projected onto -->multiple down stream visual areas, so that maps of retinal topography, or retinotopy, are maintained at multiple levels in the visual system.
Other visual functional organization that is present at birth includes maps of ocular dominance, where the responses of neuronal groups is dominated by that of one eye or the other and orientation selectivity where the responses of neighboring neurons is dominated by high contrast edges of particular orientation.
---
## Intrinsically photosensitive RGCs (containing melanopsin) are required for day/night activity cycles
<div><img src="figs/image_3a9dca9.png" height="100px"><figcaption></figcaption></div>
<div><img src="figs/image1_d74352b.png" height="100px"><figcaption></figcaption></div>
---
## The visual scene is inverted on the retina
<div><img src="figs/image2_33f6059.png" height="100px"><figcaption></figcaption></div>
<div><img src="figs/image3_aa4d6a4.png" height="100px"><figcaption></figcaption></div>
---
## Binocular visual field: species differences
* At the optic chiasm, visual information from the two sides of the head cross
* In animals with eyes on the sides of the head, the entire visual field for each side is sent to the opposite side of the brain (to the tectum)
* In forward-looking animals, the visual image is split
* An object on the right side of the visual field is seen by both left hemi-retinae (but not by the right hemi-retinae). The optic nerves leave the retinae, and at the optic chiasm, the two left hemi-retinae projections go left, while the two right hemi-retinae go right
<div><img src="figs/16-2_ae0f019.jpg" height="100px"><figcaption>Fig 16-2 Neurobiology, G.G. Matthews, Blackwell Science</figcaption></div>
---
## P type RGCs are sensitive to color contrast
<div><img src="figs/image10_9804c4d.png" height="100px"><figcaption></figcaption></div>
Note:
---
## Projection to cortex
* The visual field is projected in a retinotopic fashion
* The right visual field is projected onto the left cortex, while the left visual field is represented on the right
* The region of the fovea, because of its high sensitivity and density of cones, is represented by a huge amount of the cortex
<div><img src="figs/Fig27-9_e1cd31a.png" height="100px"><figcaption></figcaption></div>
Note:
Incr representation sound familiar? think of hand and lip representation in human somatosensory cortex we discussed a couple classes ago…
---
## Information from multiple LGN inputs are used to make cortical neuron receptive fields
* Filtering of info from multiple LGN cells is used to make simple and complex cells in visual cortex
red dots inhibitory synapses
[LGN on cell: http://www.youtube.com/watch?v=jIevCFZixIg](http://www.youtube.com/watch?v=jIevCFZixIg)
[V1 simple cell: http://www.youtube.com/watch?v=Cw5PKV9Rj3o](http://www.youtube.com/watch?v=Cw5PKV9Rj3o)
[Hubel: https://www.youtube.com/watch?v=y_l4kQ5wjiw](https://www.youtube.com/watch?v=y_l4kQ5wjiw)
<div><img src="figs/image5_3ab5bfc.png" height="100px"><figcaption></figcaption></div>
Note:
other hubel vid I saw and marked times…
* david hubel 1:24-2:18:
* 125 million rods and cones in each eye.
* misha pavel, sobel filter
* try to build a robot to see and interpret images and it's hard.
: 4:45 nice example of movement and perception of cat face
---
## Types of simple cell receptive fields
<div><img src="figs/image6_8eafbb8.png" height="100px"><figcaption></figcaption></div>
Note:
---
## Some cells are selective for the direction of movement
We use multiple types of visual information for perception:
[https://www.youtube.com/watch?v=y_l4kQ5wjiw](https://www.youtube.com/watch?v=y_l4kQ5wjiw)
<div><img src="figs/image7_50fb6ef.png" height="100px"><figcaption></figcaption></div>
Note:
others selective for movement, disparity
* david hubel 1:24-2:18:
* 125 million rods and cones in each eye.
* misha pavel, sobel filter
* try to build a robot to see and interpret images and it's hard.
: 4:45 nice example of movement and perception of cat face
---
## Maps in the visual system- ocular dominance columns and orientation selectivity in visual cortex
Ocular
dominance
Orientation
selectivity
<div><img src="figs/kandelschwartz-fig27-17_3d15d30.pdf" height="100px"><figcaption></figcaption></div>
<div><img src="figs/kandelschwartz-fig27-14_e52cde6.pdf" height="100px"><figcaption></figcaption></div>
Note:
The organization of connections from each eye is shown here where if we were to look at a chunk of primary visual cortex from ferrets, cats, or monkeys we would find ocular dominance columns where the response properties of neighboring cells is dominated by that of one eye or the other and which can be demonstrated by electrophysiological recordings or by histological staining for cytochrome oxidase.
Overlaid on this map of alternating ocular dominance columns is a map of orientation pinwheels in visual cortex shown by the isocontour lines on the surface *here* and by the colored orientation map *here* -->where the colored map represents the preferred response of neighboring neurons to high contrast edges presented at different orientations in the visual field.
---
## Columnar organization of ocular dominance
<div><img src="figs/PN12132_f1003e0.jpg" height="100px"><figcaption>Neuroscience 2e Sinauer 2001</figcaption></div>
<div><img src="figs/PN12131_f44cd94.jpg" height="100px"><figcaption>Neuroscience 2e Sinauer 2001</figcaption></div>
Note:
---
## Localization of multiple visual areas in the human brain using fMRI
<figure><img src="figs/Neuroscience5e-Fig-12.17-1R_copy_1a1c7c2.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 12.17</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-12.17-2R_copy_7168914.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 12.17</figcaption></figure>
Note:
---
## Subdivisions of the extrastriate cortex in the macaque monkey
Van Essen 1992
<div><img src="figs/ScreenShot2015-09-13at12.34.35PM_8ea399c.png" height="100px"><figcaption></figcaption></div>
<div><img src="figs/ScreenShot2015-09-13at12.33.31PM_63619a9.png" height="100px"><figcaption></figcaption></div>
Note:
but he also emphasized that “the brain is a complex of widely and reciprocally interconnected systems and that the dynamic interplay of neural activity within and between systems is the very essence of brain function”. And indeed if you look at this—> anatomical wiring diagram for different visual areas represented by different colors you will notice that we use an organized constellation of brain regions to process and route different types of visual information and each one of these brain regions consists of many thousands of these basic cortical column building blocks described on the previous slide.
---
## Grandmother neurons in the human brain?
[http://www.youtube.com/watch?v=Y7BZlDfVR6k](http://www.youtube.com/watch?v=Y7BZlDfVR6k)
Quiroga et al., Nature 2005
<div><img src="figs/ScreenShot2015-11-02at12.57.02PM_d992132.png" height="100px"><figcaption></figcaption></div>
Note:
Invariant visual representation by single neurons in the human brain. Quiroga et al., Nature 2005
Recordings were made in medial temporal lobe of the cerebral cortex including entorhinal cortex and hippocampus course of clinical procedures to treat epilepsy.
Interestingly this cell did not respond to pictures of Jennifer Aniston with Brad Pitt, maybe this cell had ‘moved on’ just like Miss Aniston. But other cells in this work did respond to selectively to Aniston with her friend’s costar Lisa Kudrow.
One object per neuron?
however these results may be best understood in a non-visual context. Some of the example cells responded not only to pictures but also to the printed name of a particular person or object. So this type of invariance must be based off learned associations.
---
## Grandmother neurons: a sparse neural code
C. Connor, Nature 2005
<div><img src="figs/ScreenShot2015-11-03at9.53.42AM_c595899.png" height="100px"><figcaption></figcaption></div>
Note:
invariant visual representation by single neurons in the human brain. Quiroga et al., Nature 2005
Connor Nature 2005, N&V on Quiroga et al:
>a more technical term for the grandmother issue is ‘sparseness’.
>At earlier stages in the object recognition pathway the neural code for an object is a broad activity pattern distributed across a population of neurons, each responsive to a discrete visual feature. At later, higher order processing stages, neurons become increasingly responsive for combinations of features and the code becomes increasingly sparse.
sparse and non-variant
---

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## The chemical senses
* Chemical Senses
* Olfaction
* Taste
* Trigeminal chemosensory
* Irritant system
Note:
phylogenetically oldest sense.
not considered very important in humans compared to other senses, but think about the fantastically strong emotional memories tied to smells— the olfactory system when robustly stimulated can have much influence over the formation of olfactory tied memories through its direct connectivity to the limbic and memory systems of the brain. We’ll learn a bit about this connectivity later.
Mucus membranes of eyes face mouth
---
## Olfaction
* The olfactory system detects airborne molecules called odorants.
* Provides information about food, self, others, animals, plants, etc.
* Influence feeding behaviors, social interactions, and even reproduction.
* Processes information about the identity, concentration, and quality of a wide range of chemical stimuli.
Note:
---
## The route of olfaction
<div style="font-size:0.8em;">
<div></div>
* Starts in the nose, odorants bind to specific receptors found in the olfactory epithelium
* Olfactory epithelium projects to neurons in the ipsilateral olfactory bulb, which in turn sends projections contra and ipsi to the piriform cortex in the temporal lobe and other forebrain structures
* Piriform cortex is only 3-layered (sometimes called the archicortex), and is considered phylogenetically older than the neocortex
* Unique among senses in that it does not include a thalamic relay between primary receptors and the cerebral cortex
* Piriform cortex relays information via the thalamus to the associational cortex to initiate motor, visceral, and emotional reactions to olfactory stimuli
</div>
Note:
---
## Human olfactory bulb
<figure><img src="figs/Neuroscience5e-Fig-15.02-2R_a10bacf.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.2</figcaption></figure>
Note:
<!-- ## Rodent brain -->
---
## The flow of olfactory information
<div><img src="figs/nobelprize-org-2004-OR_7541302.png" height="400px"><figcaption>[nobelprize.org, 2004](http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html)</figcaption></div>
Note:
---
## Organization of the human olfactory system
<figure><img src="figs/Neuroscience5e-Fig-15.01-1R_9fc2539.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.1</figcaption></figure>
Note:
---
## Olfactory perception
* Is not as acute in humans as in a number of other animals
* Less acute in humans because of a smaller variety of functional olfactory receptor proteins, less receptor neuron density, and also a lesser amount of relative cortex used to process information
* Mice have ~1000 olfactory receptor genes, humans several hundred
Note:
---
## Fun olfaction factoids
* Odors can be detected at very low concentrations (bell peppers 0.01 nM)
* Small changes in molecular structure can change perception
* Anosmics are people who cannot smell specific odors. 1/100 people cannot smell skunk, 1/10 hydrogen cyanide
Note:
---
## Human odor detection thresholds
<div>
<div></div>
Compound | Odor threshold in air (parts per billion)
--- | ---
methanol | 141,000
acetone | 15,000
formaldehyde | 870
menthol | 40
T-butyl mercaptan | 0.3
<figcaption>Devol et al., 1990</figcaption>
</div>
Note:
rats 8-50 times more sensitive to odors than humans
dogs 300-10000 times more sensitive
humans have 10 million ORNs, dogs have 1 billion
butyl mercaptan: similar to major constituent of defensive spray in skunk
tert-butyl mercaptan: natural gas additive
---
## Combinatorial coding
* Distributed code for face representation
* Color coding by S, M, L cones
* Language is combinatorial
* 26 letters gives many different words
Note:
alphabet
: a set of letters or symbols in a fixed order, used to represent the basic sounds of a language
: the basic elements in a system that combine to form complex entities
---
## The vomeronasal organ
* Many species have a specialized structure that recognizes species-specific odorants called pheromones that play important roles in innate social, reproductive, and parenting behaviors
* The vomeronasal organ (VNO) projects to the accessory olfactory bulb, which in turn projects to the hypothalamus
* The VNO is absent or not very prominent in primates (including humans) and there is debate as to whether humans detect pheromones
* In animals a lesion in the main olfactory projection leaves reproductive behaviors intact, however lesions of the VNO projection severely compromises sexual selection and dominance hierarchies
Note:
rudimentary VNO found in 8% of adults. And VNO projects to special region of ob called accessory olfactory bulb which is also largely absent in primates.
mating, aggression behaviors etc
loss of sex discrimination and male male aggression in mice without TRP2
TRP2/TRPC2: Transient receptor potential cation channel, subfamily C, member 2. Not expressed in humans
Stowers, L.; Holy, T. E.; Meister, M.; Dulac, C.; Koentges, G. (2002). "Loss of sex discrimination and male-male aggression in mice deficient for TRP2". Science 295 (5559): 1493–1500. Bibcode:2002Sci...295.1493S. doi:10.1126/science.1069259.
[http://science.sciencemag.org/content/295/5559/1493.full-text.pdf+html](http://science.sciencemag.org/content/295/5559/1493.full-text.pdf+html)
---
## Pheromones and the VNO
<figure><img src="figs/Neuroscience5e-Box-15B-0_ac55b96.jpg" height="400px"><figcaption>Neuroscience 5e Box 15B</figcaption></figure>
Note:
---
## Mouse pheromones
Record from a neuron in the AOB, pink area is when mouse is sniffing at face. Yellow are is when sniffing genitals.
<div><img src="figs/image1_9b348ce.png" height="400px"><figcaption>[Lou and Katz Science 2003](http://www.sciencemag.org/cgi/content/full/299/5610/1196/DC1)</figcaption></div>
Note:
---
## Human pheromones?
* Female rodents (mice) grouped together synchronize their estrous cycle upon exposure to pheromones in male mouse urine (‘Whitten effect’). This depends on pheromone receptors and VNO—>AOB connectivity.
* VNO is vestigial in humans: VRs and TRPC2 are pseudogenes
* Myth: women who live in close proximity synchronize their menstrual cycle (the ‘McClintock effect’, after McClintock, Nature 1971). The current scientific evidence for this effect in human is not strong.
* However there’s some evidence for odorants working as pheromone-like molecules to influence behaviors (attraction, fear) mediated by the main olfactory system
Note:
Human pheromones??
vestigial. VNO anatomy is non-functional in human.
myth of mcclintock effect. statistical issues with these studies, no one has reported human estrous cycle synchrony over more than 6-9 months as indeed the original study was on college women at wellsey over the period of one academic calendar year. Windshield wiper, coupled oscillator analogy. Just out of phase.
But other animals…
And olfactory cues that aren’t necessarily odorless certainly can affect our behavior and pheromone like molecules may act through our olfactory system
[from: http://www.sciencedirect.com/science/article/pii/S2090123211000397](http://www.sciencedirect.com/science/article/pii/S2090123211000397)
mother-child interactions at birth
[from http://www.ncbi.nlm.nih.gov/books/NBK55967/](http://www.ncbi.nlm.nih.gov/books/NBK55967/)
> Different works have shown that odor-cued memories are more emotional than memories triggered by visual or verbal cues
from one website:
Pheromones are naturally occurring odorless substances the fertile body excretes externally, conveying an airborne signal that provides information to, and triggers responses from, the opposite sex of the same species.
oxford dictionary doesn’t include the word ‘odorless’.
wikipedia: A pheromone (from Ancient Greek φέρω phero "to bear" and hormone, from Ancient Greek ὁρμή "impetus") is a secreted or excreted chemical factor that triggers a social response in members of the same species.
>the adult human VNO, in different studies, has been reviewed as non-functional as it contains few neurons and has no sensory function where no cells were shown to express olfactory marker protein, have synaptic contacts or have evidence for a nerve connecting to/from the VNO
VNO is vestigial in humans: VRs and TrpC2 are pseudogenes
myth: women who live in close proximity synchronize their menstrual cycle (the McClintock effect, McClintock, Nature 1971)
However there’s some evidence for pheromone like molecules and behaviors (attraction, fear) mediated by the main olfactory system
whitten effect: exposure of grouped female mice to phermones in male mouse urine synchronizes their estrous cycle. The pheromones in male urine are dependent on male sex hormones like testosterone.
[from http://www.informatics.jax.org/silver/chapters/4-3.shtml](http://www.informatics.jax.org/silver/chapters/4-3.shtml)
>The normal estrus cycle of a laboratory mouse is 4-6 days in length
vandenburgh effect: early estrous cycle induction in prepubertal female mice exposed to urine from dominant male
lee-boot effect: suppression or prolongation of estrous cycle in female mice (and other rodents) when mice housed in groups and isolated from other males
bruce effect: female mouse pregnancy termination from exposure to scent of unfamiliar male
[http://www.ncbi.nlm.nih.gov/pubmed/22087345](http://www.ncbi.nlm.nih.gov/pubmed/22087345)
>Latent toxoplasmosis, a lifelong infection with the protozoan Toxoplasma gondii, has cumulative effects on the behaviour of hosts, including humans. The most impressive effect of toxoplasmosis is the "fatal attraction phenomenon," the conversion of innate fear of cat odour into attraction to cat odour in infected rodents.
phylogenetic distance human, mouse, rat:
[from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524408/ 2003](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524408/)
>human and rodents diverged ∼75 million years ago, whereas mouse and rat diverged ∼12-24 million years ago[Waterston et al. 2002; Rat Sequencing Project Consortium 2004]
-human has equal genetic distance from both rodents
-human has been evolving from human/rodent common ancestor at slower rearrangement rate and thus has a more ancestral genome
>Rat Closer to Human?
>rearrangement differences between the two rodents suggest that, except for the small inversions, overall, the rat genome might have a structure on a large scale closer to the human genome than the mouse genome.
>lacking the extra interchromosomal changes of mouse (Table 3), many rat fragments are closer to human.
>In terms of chromosome morphology (and possibly the genome size as well), rat is also between mouse and human.
[from https://www.genome.gov/11511308 2012](https://www.genome.gov/11511308)
Humans have 23 pairs of chromosomes, while rats have 21 and mice have 20.
>all three organisms to be related to each other by about 280 large regions of sequence similarity - called "syntenic blocks" - distributed in varying patterns across the organisms' chromosomes.
> 50 chromosomal rearrangements occurred in each of the rodent lines after divergence from their common ancestor
>number of chromosomal rearrangements, as well as other types of genome changes, was found to be much lower in the primate lineage, indicating that evolutionary change has occurred at a faster rate in rodents than in primates.
---
## Olfactory receptors
* Discovered by Linda Buck and Richard Axel. Shared nobel prize in 2004
* They found that olfactory receptors comprise a large GPCR gene family (~1000 olfactory receptors)
* Each olfactory neuron expresses a single olfactory receptor (even inactivates one copy of each allele)
* Each receptor can bind to multiple odorants
* Each neuron that expresses a given receptor targets to the same glomeruli in the olfactory bulb
Note:
Linda Buck and Richard Axel "for their discoveries of odorant receptors and the organization of the olfactory system"
---
## Olfactory receptors
<figure><img src="figs/Neuroscience5e-Fig-15.09-1R_copy_3521e8e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.9</figcaption></figure>
Note:
---
## Olfactory receptors
<figure><img src="figs/Neuroscience5e-Fig-15.09-2R_copy_fde3d57.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.9</figcaption></figure>
Note:
red arrows indicate intron locations of splice sites in other animals. Mammalian genes for ORs lack introns.
largest single known gene family in all mammals. Representing 3-5% of genome. Perhaps 60% of these 950 OR genes are not transcribed in humans and chimps rendering them pseudogenes, vs 15-20% in mice and dogs.
pseudogene
: sequence of DNA containing a promoter and transcription initiation site, but due to sequence changes the DNA cannot be transcribed into a stable mRNA or the transcript cannot be translated into a protein.
---
## Anatomy of the olfactory epithelium
<figure><img src="figs/Neuroscience5e-Fig-15.07-1R_79a296a.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.7</figcaption></figure>
Note:
---
## ORN receptor potentials generated in cilia
<figure><img src="figs/Neuroscience5e-Fig-15.08-0_2a03d42.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.8</figcaption></figure>
Note:
---
## ORNs are continuously generated from basal cells
* Turnover of 6-8 weeks in rodents
* Susceptible to pollutants, allergens...
* Source of neural stem cells
<figure><img src="figs/Neuroscience5e-Fig-15.07-3R_copy_d15b3aa.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 15.7</figcaption></figure>
Note:
basal cells and progeny in labeled in red
blue is all cell nuclei
green for OMP at right
---
## Olfactory receptor signal transduction
* Binding of odorant to receptor activates a Gα (Called G-olf) that in turn activates adenylyl cyclase
* cAMP gates a Na+/Ca2+ cation channel. Calcium rushes in and activates a Cl- channel. Chloride normally high in-low out in olfactory neurons and thus Cl- leaving also depolarizes cell
Note:
---
## Olfactory receptor signal transduction
<figure><img src="figs/Neuroscience5e-Fig-15.11-1R_a07ccab.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.11</figcaption></figure>
Note:
How would you desensitize odorant pathway? PDE, Ca-Cam blocks cAMP channel
Adaptation comes from calmodulin binding up the Ca2+ and closing
Cl- channels and also from being pumped out.
---
## Molecules critical to odorant signal transduction
<figure><img src="figs/Neuroscience5e-Fig-15.11-2R_ecf5538.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.11</figcaption></figure>
Note:
Minty odor
EOG electroolfactorogram
---
## A single olfactory receptor can be activated by single or groups of stimuli
<figure><img src="figs/Neuroscience5e-Fig-15.12-0_4019559.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.12</figcaption></figure>
Note:
Eucholipyol, banana oil
But there is also broad OSN tuning--
* Primary olfactory sensory neurons are broadly tuned to odorants
* Sicard and Holley (1984) Brain Research 292:283
Eucalyptol is cineole
Camphor is the smell of turpintine. Aromatic
---
## Dogs smell better than humans
<figure><img src="figs/Neuroscience5e-Fig-15.02-1R_copy_cf5395a.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 15.2</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-15.03-0_copy_398483b.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 15.3</figcaption></figure>
Note:
---
## Olfactory system summary video
<div><video height=400px controls src="figs/Animation15-01TheOlfactorySystem.mp4"></video><figcaption>Neuroscience 5e Animation 15.1</figcaption></div>
Note:
---
## The olfactory bulb
* A small structure above the nasal passages
* Site where sensory information is collected and gets sorted
* Sensory neurons project to glomeruli
* Olfactory receptor neurons synapse onto the dendrites of mitral cells which then project to the cerebral cortex
Note:
ORNs that carry same olfactory receptors converge upon same glomeruli (Mombaerts et al Cell 1996)
---
## Olfactory receptors are localized into discreet areas
<div><img src="figs/image3_7693919.jpg" height="200px"><figcaption></figcaption></div>
<figure><figcaption class="big">olfactory cilia, all ORNs, I7 ORNs, M71 ORNs</figcaption><img src="figs/Neuroscience5e-Fig-15.10-0_copy_3bcd339.jpg" height="200px"><figcaption>Neuroscience Fig. 15.10</figcaption></figure>
Note:
omp (green all ORNs). Adenylyl cyclase II (red) limited to olfactory cilia
all ORNs
I7 ORNs
M71 ORNs
---
## Localization preserved in the olfactory bulb
<div><img src="figs/image4_e4638ef.jpg" height="400px"><figcaption></figcaption></div>
Note:
* fig from luo principals of neurobiology?
---
## Subtle changes in a molecules structure can be detected by different receptors
* Johnson, Woo, Hingco, Pham and Leon (1999) J. Comp. Neurol. 409:529
* n-amyl acetate, (control)
* Acetic acid, (2)COOH
* Propanoic acid, (3)COOH
* Butanoic acid, (4)COOH
* Pentanoic acid, (5)COOH
* Hexanoic acid, (6)COOH
Note:
* acid series of similar structures
* 2-deoxyglucose activation patterns in the rat olfactory bulb in response to an aliphatic acid series
* Johnson, Woo, Hingco, Pham and Leon (1999) J. Comp. Neurol. 409:529
---
## Neurons of olfactory bulb
* Mitral cell, dendrites to a single glomerulus and axon to brain
* Tufted cell contacts multiple glomeruli
* Interneurons (PG) also participate in processing (inhibition)
* Bulb also gets info from the cortex
<figure><figcaption class="big">Mitral Cell, MC. Tufted Cell, TC. Granule cell, GC. Periglomerular Cell, PG.</figcaption><img src="figs/olfactorybulbwiring_43ed7c4_copy_ab80a23.jpg" height="200px"><figcaption></figcaption></figure>
Note:
* fig origin unknown. No find through image search
---
## Neurons of olfactory bulb
<div><figcaption class="big">Periglomerular cells</figcaption><img src="figs/periglomerular_04f528f.png" height="400px"><figcaption>J. Ackman 2003</figcaption></div>
Note:
---
## Olfactory pathways
* OB axons go to piriform (olfactory) cortex, amygdala (fear), entorhinal cortex (hippocampus, memory)
* VNO axons go directly to amygdala (fear)
<figure><img src="figs/olfactorypathways_dfe0730_copy_d011baa.jpg" height="300px"><figcaption></figcaption></figure>
Note:
* fig origin unknown. No find through image search
---
## Organization of the human olfactory system
* piriform ctx and OFC: conscious odor perception, multimodal association
* olfactory tubercle: reward, motivation
* amygdala, hypothalamus: fear, aggression, feeding, reproduction
* entorhinal ctx, hippocampal formation: memory
<div><img src="figs/Neuroscience5e-Fig-15.01-3R_3252af3.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 15.1</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-15.01-2R_8ff6462.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 15.1</figcaption></div>
Note:
piriform ctx and OFC: conscious odor perception, multimodal association
olfactory tubercle: reward, motivation
amygdala, hypothalamus: fear, aggression, feeding, reproduction
entorhinal ctx, hippocampal formation: memory
---
## Taste (gustation)
* Used to determine whether food should be ingested (together with smell, touch, and pain).
* Provides information about the identity, concentration, and pleasant or unpleasant quality of a substance.
* Works together with the GI system to get it ready to receive food (saliva and swallowing) or reject food (regurgitation).
* Information of texture and temperature of things in mouth processed by somatic sensory system receptors.
* Contains both peripheral receptors and central processing.
Note:
---
## The gustatory system
<figure><img src="figs/Neuroscience5e-Fig-15.17-1R_0025e07.jpg" height="400px"><figcaption></figcaption></figure>
Note:
These afferent fibers all end in the nucleus of the solitary tract (NST) in the medulla. From there the information flows mainly to the thalamus and then to the gustatory cortex.
pathways
* afferents from tongue and epiglottis to gustatory nucleus (in medulla next to 4th ventricle, part of solitary nuclear complex) and then to VPM
* from taste bud to solitary nuclear complex and then to VPM
* Solitary nuclear complext to nucleus ambiguous to salivary glands
* Other somatosensory to parabrachial nuclei
---
## Cortical projections of gustatory pathway
<figure><img src="figs/gustatorycentralpathways_2d4c5ae_copy_2f00775.jpg" height="400px"><figcaption></figcaption></figure>
Note:
* fig origin unknown.
From the VPM projections reach the gustatory cortex: anterior insular cortex and frontal operculum.
Information derived from different areas of the tongue is spatially segregated in the n. of the solitary tract, the thalamus, and the cortex. (Still true?)
---
## Gustatory cortex
* Primary somatosensorycortex (Postcentral gyrus)
* Gustatory Cortex (frontal operculum andanterior insular cortex)
* Fronto-parietal operculum
* Lateral sulcus
* Insular cortex
<div><img src="figs/gustatorycortex_52762a1_copy_ffa872c.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/gustatorycortexscheme_0fbbbe3_copy_d0e2238.jpg" height="100px"><figcaption></figcaption></div>
Note:
* fig origin unknown.
Note that the gustatory cortex is very close to the tongue area on the somatosensory cortex!
---
## Organization of the gustatory system
<figure><img src="figs/Neuroscience5e-Fig-15.17-2R_c37e52e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.17</figcaption></figure>
Note:
---
## Taste perception
* Most tastes are hydrophilic molecules solubilized in saliva
* Tastants include salts, amino acids, sugars, acids, plant alkaloids
* quantity of substance also perceived, the higher the concentration the more intensity the taste
* Tastants act in the millimolar range, except for bitter things (strychnine 0.1 µM)
* The tongue is not strictly regionalized by taste although some areas are more sensitive than others
Note:
---
## 5 basic tastes
* Sweet (sucrose, aspartame, glycine, etc.)
* Sour (H+)
* Salty (Na+, some other salts)
* Umami (savory, glutamates)
* Bitter (alkaloids)
<figure><img src="figs/five-tastes_copy_93d5298.jpg" height="100px"><figcaption></figcaption></figure>
Note:
* fig origin unknown. No find through image search
---
## The organization of the taste system
* Taste receptors are organized in taste buds
* Taste buds contain between 30-100 taste cells
* 75% of all taste buds are found in papillae
* 3-types: fungiform (25%, localized in anterior tongue), circumvallate (50%, rear of tongue) and foliate (25%, posterolateral edge)
* There is great variability in the human population with respect to the number of taste buds
Note:
---
## Tongue anatomy
<figure><img src="figs/Neuroscience5e-Fig-15.18-1R_495eb15.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.18</figcaption></figure>
Note:
Types of papillae:
Circumvallatepapillae
Foliatepapillae
Fungiformpapillae
---
## Structure of a taste bud
<figure><img src="figs/Neuroscience5e-Fig-15.18-2R_ae72520.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.18</figcaption></figure>
Note:
---
## Tastes
<figure><img src="figs/Neuroscience5e-Fig-15.19-0_41ee554.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.19</figcaption></figure>
Note:
Composite fMRI image showing different locations of activation in insular cortex to each of these tastes.
---
## Taste receptors
* 5 distinct classes of taste receptors
* Salty and sour generally transduced by ions (Na+ or H+) that open channels
* This depolarizes neuron, that then leads to opening of voltage gated Na+ channels
* This depolarizes neuron more and leads to opening of voltage gated Ca2+ channels
* Leads to the release of serotonin
Note:
---
## Transduction mechanisms in a generic taste cell
<figure><img src="figs/Neuroscience5e-Fig-15.20-0_505080d.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 15.20</figcaption></figure>
Note:
---
## Taste receptors
* Sweet and Unami receptors are GPCRs that share a subunit called T1R3
* T1R3 is paired with T1R2 for sweet and T1R1 for amino acids
* T1R1 and T1R2 are expressed in non-overlapping neurons
* T1R2/3 activation leads to activation of PLC, increases IP3 and opens Ca2+channels (TRPM5). Ca2+ channel opening depolarizes cell
* Bitter taste receptors (T2R) have 30 subtypes. Multiple members are expressed in same neurons but not in same neurons as the others. These use a specific Gα called gustucin
Note:
---
## Taste receptors
<figure><img src="figs/Neuroscience5e-Fig-15.21-0_copy_3a88321.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.21</figcaption></figure>
Note:
---
## Taste coding specificity and segregated representation
<figure><img src="figs/Neuroscience5e-Fig-15.22-0_copy_8088d1f.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 15.22</figcaption></figure>
Note:
sweet a.a. and bitter receptors are expressed in diff subsets of taste cells.
gene from the TRPM5 channel is inactivated in ko mice and behavioral responses measured with taste preference test. Mouse gets two drinking spouts (one with water and one with tastant and relative frequency of licking is measured).
pleasant tastes (sugar and umami), incr concentration gives incr response. For bitter there is decr response.
KO the PLCB2 (phospholipase) and responses are eliminated to sweet, umami, and bitter but rescuing expression only in T2R expressing cells recovers just the bitter taste response to wildtype levels.
* Sour receptor is expressed in every taste bud but isn’t in the same neurons as other receptors
* An experiment to show that T1R2 is a sweet receptor and PKD2L1 is a sour receptor
* Taste pathways remain segregated in the cortex (Zuker lab imaging?)
---
## Putting the bitter receptor into sweet receptor neurons will cause mice to be attracted to bitter!
<div><img src="figs/image16_190e843.png" height="300px"><figcaption>Based on Fig. 5 from Zhang et al., Cell 2003</figcaption></div>
Note:
Based on/adapted from Fig. 5 from Zhang et al., Cell 2003
[http://www.sciencedirect.com/science/article/pii/S0092867403000710](http://www.sciencedirect.com/science/article/pii/S0092867403000710)
And the Zuker lab has recently silenced specific brain areas for bitter and sweet in mouse to alter perceptive sense of these tastes:
[http://newsroom.cumc.columbia.edu/blog/2015/11/18/scientists-turn-tastes-on-and-off-by-activating-and-silencing-clusters-of-brain-cells/](http://newsroom.cumc.columbia.edu/blog/2015/11/18/scientists-turn-tastes-on-and-off-by-activating-and-silencing-clusters-of-brain-cells/)
Peng et al, Nature 2015
[http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature15763.pdf](http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature15763.pdf)
---
## Stimulation of the ‘bitter’ taste cortex is sufficient to make a mouse pucker
<div><img src="figs/ScreenShot2016-02-22at4.43.22PM_712d13b.png" height="400px"><figcaption>[Video 1 from Peng et al., Nature 2015](http://www.nature.com/nature/journal/vaop/ncurrent/fig_tab/nature15763_SV1.html)</figcaption></div>
Note:
Based on/adapted from Fig. 5 from Zhang et al., Cell 2003
[http://www.sciencedirect.com/science/article/pii/S0092867403000710](http://www.sciencedirect.com/science/article/pii/S0092867403000710)
And the Zuker lab has recently silenced specific brain areas for bitter and sweet in mouse to alter perceptive sense of these tastes:
[http://newsroom.cumc.columbia.edu/blog/2015/11/18/scientists-turn-tastes-on-and-off-by-activating-and-silencing-clusters-of-brain-cells/](http://newsroom.cumc.columbia.edu/blog/2015/11/18/scientists-turn-tastes-on-and-off-by-activating-and-silencing-clusters-of-brain-cells/)
Peng et al, Nature 2015
[http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature15763.pdf](http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature15763.pdf)
Bradbury J (2004) Taste Perception: Cracking the Code. PLoS Biol 2(3): e64. [doi:10.1371/journal.pbio.0020064](http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020064)
---
## The physiology of flavor perception
* Responses from taste and smell are first combined in the orbital frontal cortex (OFC)
* OFC also receives input from the primary somatosensory cortex and the inferotemporal cortex in the visual what pathway
* Bimodal neurons in this area respond to taste and smell as well as taste and vision
* Firing of these neurons is also affected by the level of hunger of the animal for a specific food
<figure><img src="figs/MRI_jba1-OFC_copy_8a13a73.jpg" height="100px"><figcaption></figcaption></figure>
Note:
---
## Multimodal integration in orbitofrontal cortex
<figure><img src="figs/orbitofrontal-cortex-pathways_4393768.png" height="400px"><figcaption></figcaption></figure>
Note:
The orbital frontal cortex (OFC) receives inputs from vision, olfaction, and touch, as shown. It is the first area where signals from the taste and smell systems meet. (info based on E. T. Rolls (2000). The orbitofrontal cortex and reward. Cerebral Cortex, 10, 284-294, Fig. 2.)
---

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## Movement
* Movement is the planning, coordination & execution of a motor program that relies on information provided by the sensory system
* Movement is controlled by the motor systems of the brain and spinal cord
* Motor systems translate neural signals into contractile force in muscles
* Allows us to maintain balance and posture, move our body, limbs, eyes, tongue & communicate through speech
Note:
---
## Types of movement
* Reflex responses– knee jerk, withdrawal from pain, swallowing. Muscle contractions and relaxations that are rapid, stereotyped, involuntary and coordinated
* Rhythmic motor patterns– walking, running, chewing. Typically initiation and termination are voluntary and triggered by peripheral stimuli
* Voluntary movements– initiated movements to accomplish a specific goal (e.g. piano playing, writing). These are goal directed and largely learned movements that improve with practice, as one learns to anticipate and correct for environmental obstacles
Note:
---
## Overall organization of neural structures that control movement
<figure><img src="figs/Neuroscience5e-Fig-16.01-0_copy_c8e6e7d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.1</figcaption></figure>
Note:
---
## Control of movement
* Motor systems responsible for the control of movement can be divided into four distinct but highly interactive subsystems
* Lower motor system– Gray matter of spinal cord and brainstem-contain lower motor neurons and lower circuit neurons. The final common path of all motor output
* Upper motor systems– Send information to spinal cord and brain stem, initiate voluntary movements. Contains motor cortex and some brainstem centers
* Cerebellum– No direct access to lower motor systems. Connects to upper motor systems. Responsible for motor learning
* Basal ganglia– Suppresses unwanted movements and primes neurons for the initiation of movements. Parkinson’s and Huntington’s diseases affect the basal ganglia
Note:
---
## Muscles
* Relaxation and contraction
* Muscles can pull but not push. Thus separate sets of muscles at the opposite sides of joints must mediate flexion or extension
* Movements at a joint engage two opposing sets of muscles
Note:
Muscles only pull they do not push, therefore we have opposing/antagonistic muscles
EMG– electromyograph, measures electrical activity in muscles. Bicep/tricep figure with EMG histogram around elbow joint.
---
## Coupling of excitation and contraction
* Action potential in motor axon
* End plate potential at neuromuscular junction
* Action potential in muscle fiber
* The AP in the muscle fiber is followed by a twitch in the muscle fiber
* Twitch– transient all-or-none contraction
Note:
* Each muscle fiber is innervated by only one motor neuron. Group of muscle fibers in a muscle innervated by a single motor neuron is a motor unit
* twitch happens after small small latency, 5-10 ms
TODO: motor neuron AP --> muscle fiber EPP --> muscle fiber AP. AP and Vm in muscle fiber, latency, and muscle tension rise and decay
---
## Organization of lower motor neurons in the ventral horn of the spinal cord
<div style="width:300px"><figcaption class="big">gastrocnemius, soleus muscle</figcaption><img src="figs/Gray438_3f6f3c0.png" height="400px"><figcaption>Gray's Anatomy</figcaption></div>
<div><figcaption class="big">retrograde motor neuron labeling</figcaption><img src="figs/Neuroscience5e-Fig-16.02-0_348e464.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.2, Burke et al., 1977</figcaption></div>
Note:
* Motor neurons id. by injecting a retrograde tracer into medial gastrocnemius or soleus muscle of cat. Labels neuronal cell bodies and their spatial distribution
* Lower motor neurons form distinct clusters (motor pools)
---
## Motor pools
<div style="font-size:0.7em;width:400px">
<div></div>
* Retrograde labeling of muscles show that the cell bodies of motor neurons are found in ventral horn of the spinal cord
* Each motor neuron innervates muscle fibers within a single muscle
* All the motor neurons innervating a single muscle are grouped together in clusters called motor pools
* Motor pools are located with a slight spread along the A-P axis
* There is topography along medial-lateral axis of the spinal cord. Neurons that innervate axial musculature (trunk) are located medially, neurons that innervate distal muscles are located laterally
</div>
<div><img src="figs/Neuroscience5e-Fig-16.02-2R_4c73db7.jpg" height="400px"><figcaption>Neuroscience 5e Fig 16.2</figcaption></div>
Note:
---
## Somatotopic organization of lower motor neurons in the ventral horn
<figure><img src="figs/Neuroscience5e-Fig-16.03-0_e7b6c42.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.3</figcaption></figure>
Note:
somatotopic mapping of body parts
---
## Location of local circuit neurons that supply the medial region of the ventral horn
<div style="width:400px">
<div></div>
* Medially localized local circuit motor neurons deal with posture, project over a few segments both contra and ipsilaterally
* Lateral circuit motor neurons deal with fine movements, project ipsilaterally
</div>
<div><img src="figs/Neuroscience5e-Fig-16.04-0_a8cdffa.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.4</figcaption></div>
Note:
---
## Types of motor neurons
* α motor neurons– innervate the extrafusal muscle fibers, the striated muscle fibers that generate the forces needed for movement
* γ motor neurons– innervate specialized muscle fibers in the muscle spindles that are embedded within connective tissue in the muscle, known as intrafusal muscle fibers. These fibers are also innervated by sensory axons that send info to the brain and spinal cord about the length and tension of muscle
Note:
---
## Amyotrophic lateral sclerosis (ALS)
* 'Lou Gehrig’s disease'
* A disease of α- motor neurons and upper motor neurons
* 30,000 Americans have it at any given time
* Both genetic and spontaneous mechanisms to contract ALS
* Superoxide dismutase (SOD1) is a gene that when mutated leads to ALS (autosomal dominant)
Note:
axon transport disease in neurons with long axons
Superoxide dismutase
: enzyme
: helps break down potentially harmful oxygen molecules in cells
---
## The motor unit
* A motor unit is the sum total of extrafusal skeletal muscle fibers within a muscle that are innervated by a single α motor neuron
* An action potential normally brings to threshold all muscle fibers it contacts
<figure><img src="figs/Neuroscience5e-Fig-16.05-0_copy_a05954b.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 16.5</figcaption></figure>
Note:
motor unit
* motor unit in soleus (important for posture) has ~180 muscle fibers/per motor neuron
* gastrocnemius has large and small motor units with 1000-2000 muscle fibers per motor neuron. Generates forces for sudden changes in body position.
* extraocular motor units very small (~3 fibers/unit). High proportion of fibers that can contract at max velocity
* but lots of use dependent motor unit plasticity (atheletes, hypogravity conditions)
<!--
motor unit in mouse skeletal muscle
Green: α-motor neuron
Red: endplates
<div><img src="tmp/image2_3eab4b6.png" height="100px"><figcaption>unknown origin</figcaption></div> -->
---
## Types of motor units
* Slow (S) motor unit– Small motor neurons innervate relatively few muscle fibers and generate small forces. They innervate small “red” muscle fibers that contract slowly but are relatively resistant to fatigue. These are rich in mitochondria and myoglobin, and are important for activities that require sustained muscular contraction such as posture
* Fast fatigable (FF) motor unit– Large motor neurons innervate larger, more powerful units. Larger α motor neurons innervate larger pale muscle fibers that generate more force, have sparse mitochondria and are easily fatigued
* Fast fatigue-resistant (FR) motor unit– are of intermediate size, not as fast as FF units but less fatigable
Note:
* oxidative metabolism in slow type I to generate ATP, more mitochondria, greater capillary density
* type II are less oxidative more glyolytic by storing glycogen, white due to low myoglobin.
* muscles have short term energy store in creatine phosphate that is used to regenerate ATP from ADP with creatine kinase
* Glucose used for glycolysis anaerobically forming 2ATP and 2 lactic acid molecules. Fat globules during anaerobic excercise. For aerobic conditions lactate not formed, pyruvate and citric acid instead
myoglobin
: related to hemoglobin
: iron and O2 binding pigment protein in muscle tissue
: cetaceans have particular high abundance of myoglobin
: not found as much in smooth muscle
neuroglobin
: present in neurons, maybe astrocytes
: seals
: CSF
: structure determined for human in 2003 and mouse soon after
: NO dynamics, neuron survival under reduced O2 conditions?
--
## Skeletal muscle fiber types
* Histochemical staining for myosin ATPase at different shows the different fiber types
* Type I slow (innervated by S pools) are darkest at low pH
* Type IIa fast fatigable are lightest
* Type IIx (IIb in other mammals) fast fatigue-resistant are light to intermediate in staining
<figure><figcaption class="big">human diaphragm myofiber myosin ATPase histology, pH 4.60</figcaption><img src="figs/Levine_JAppliedPhysiol2002-Fig1a_copy_07561a2.jpg" height="200px"><figcaption>Levine et al., *J Applied Physiol* 2002 Fig. 1a. 50 µm scalebar</figcaption></figure>
Note:
Variation in histochemical staining for myosin ATPase activity at different pHs for the fiber types due to different Myosin heavy chain (MHC) type in the type I, IIa, IIx (formerly IIb) fibers.
IIb not actually expressed humans, but in other mammals. Human MHC IIb is actually IIx [Smerdu-1994]
Type II includes IIa, IIax, IIx, IIc (other species)
Muscles made up of fascicles, which are multiple bands of cells called muscle fibers. During development muscle fibers form from fusion of several myoblasts into long multinucleated cells. Cell size can then be regulated thereafter (e.g. with excercise). But no new muscle cells are added.
Myosatellite cells are between basemente membrane and sarcolemma of muscle fibers. Normally quiescient, but can become activated by exercise or pathology and provide extra myonuclei for muscle growth and repair[#Zammit-2006].
* Sexually dimorphic muscles include the perineal, masticatory, laryngeal muscles [#Berchtold-2000]
* hypogravity conditions affects mostly postural muscles. Body core [#Berchtold-2000]
* hypogravity conditions induced by walking on crutches or hindlimb suspension results in reduced muscle mass and strength [#Berchtold-2000]
* reduction more pronounced in extensors than in flexors [#Berchtold-2000]
[Smerdu-1994]: Smerdu, V; Karsch-Mizrachi, I; Campione, M; Leinwand, L; Schiaffino, S (Dec 1994). "Type IIx myosin heavy chain transcripts are expressed in type IIb fibers of human skeletal muscle.". The American journal of physiology. 267 (6 Pt 1): C1723–8. PMID 7545970.
[#Zammit-2006]: Zammit, PS; Partridge, TA; Yablonka-Reuveni, Z (November 2006). "The skeletal muscle satellite cell: the stem cell that came in from the cold.". Journal of Histochemistry and Cytochemistry. 54 (11): 1177–91. doi:10.1369/jhc.6r6995.2006. PMID 16899758.
[#Berchtold-2000]: Berchtold, M. W., Brinkmeier, H., and Müntener, M. (2000). Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease, Physiol Rev, 80(3), 1215-65. PMID 10893434
---
## Force and fatiguability of the three different types of motor units
Stimulation of single α motor neurons from different classes
<div><figcaption class="big">Single stimulation</figcaption><img src="figs/Neuroscience5e-Fig-16.06-1R_copy_6efefad.jpg" width="250px"><figcaption>Neuroscience 5e Fig. 16.6, after Burke et al, 1974</figcaption></div>
<div><figcaption class="big">Repetitive stimulations</figcaption><img src="figs/Neuroscience5e-Fig-16.06-2R_copy_292d625.jpg" width="250px"><figcaption></figcaption></div>
<div><figcaption class="big">Time to fatigue (minutes)</figcaption><img src="figs/Neuroscience5e-Fig-16.06-3R_copy_ba9ac85.jpg" width="250px"><figcaption></figcaption></div>
Note:
-muscle tension in resp to single AP
-change in tension in resp to repetitive stimulation. Notice summation
- notice time axes in right
---
## Contributions to muscle tension
* Size principle– more stimulation leads to more contraction (force produced) by the muscle
* At low stimulation, only slow groups are recruited. Additional stimulation recruits FR, while FF are recruited by the highest stimulation
* Provides a range of forces to perform different motor tasks
* Frequency of action potentials also plays a role in muscle tension. If muscle fibers are activated by a new action potential before they have had time to fully relax from the previous time, they produce more force
Note:
---
## Recruitment of motor neurons to medial gastrocnemius (leg muscle)
<figure><img src="figs/Neuroscience5e-Fig-16.07-0_bdee1a0.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.7, after Walmsley et al., 1978</figcaption></figure>
Note:
slow for standing
FR for walking or running
FF for sprinting, jumping
---
## Motor unit activity as voluntary force is increased
<figure><figcaption class="big">small motor units ----> large motor units</figcaption><img src="figs/Neuroscience5e-Fig-16.09-0_9a2c45a.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.9, after Monster and Chan 1977</figcaption></figure>
Note:
* This is in the human hand
* low threshold motor units gen least amount of force and are first
---
## Summation of force as a function of stimulation rate
<figure><img src="figs/Neuroscience5e-Fig-16.08-0_copy_35eb48f.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 16.8</figcaption></figure>
Note:
-id. twitches
- higher freq, tet stim gives sum of twitches to produce greater force
---
## Spinal reflexes
* Simple reflexes are stereotyped movements elicited by the activation of skin or muscle receptors, and are the basic unit of movements (Charles Sherrington, 1906)
* Complex sequences of movements can be produced by combining simple reflexes
<div><img src="figs/Neuroscience5e-Fig-01.07-1R-stretch-reflex-edit_c4d4d1a.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 1.7</figcaption></div>
Note:
myotactic reflex, first lecture.
---
## The muscle spindle: a sensory organ for determining muscle length and stretch
<div><img src="figs/Neuroscience5e-Fig-16.10-1R_copy_cc1a978.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.10</figcaption></div>
Note:
* spindle is organ for stretch
* spindles comprise 8-10 intrafusal fibers
* nuclear bag fibers
* dynamic subclass
* static subclass
* most spindles have 2-3 bag fibers
* nuclear chain fibers
* most spindles have 4-6+ chain fibers
Ia afferent activity
: mostly from dynamic type of nuclear bag fiber
: phasic response
: emphasize velocity of stretch
II afferents
: innervate static nuclear bag fibers and nuclear chain fibers
: signal sustatined fiber stretch by firing tonically, little dynamic sensitivity
: muscle tone
There are also dynamic and static classes of gamma momtor neurons
helps form negative feedback loop
--
## Types of somatosensory afferents
<div style="font-size:0.8em;">
<div></div>
sensory function | receptor type | afferent axon type | axon diameter (µm) | conduction velocity (m/s)
--- | --- | --- | --- | ---
proprioception | muscle spindle | Ia, II (**myelinated**) | 13–20 | 80–120
touch | Merkel, Meissner, Pacinian, and Ruffini cells | A𝛽 (**myelinated**) | 6–12 | 35–75
pain, temperature | free nerve endings | Aδ (**myelinated**) | 1–5 | 5–30
pain, temperature, itch | free nerve endings | C (**unmyelinated**) | 0.2–1.5 | 0.5–2
</div>
---
## The stretch reflex
<figure><img src="figs/Neuroscience5e-Fig-16.10-2R_6ba2d2b.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 16.10</figcaption></figure>
Note:
---
## The stretch reflex
* Large diameter sensory fibers (Ia afferents, fast) are coiled around muscle spindles
* Stretch imposed on a muscle stretches intrafusal muscle fibers, which in turn initiates action potentials by activating mechanically gated ion channels in Ia axons
* Ia sensory neurons synapse with motor neurons in the ventral horn of the spinal cord that innervate the same muscle (homonymous muscle) or synergistic muscles
* Ia sensory neurons activate local inhibitory connections for the antagonistic muscles
Note:
---
## The stretch reflex
<figure><img src="figs/Neuroscience5e-Fig-16.10-3R_b5c7cb2.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.10</figcaption></figure>
Note:
* So next time your boss says why are you standing around doing nothing, just say that you're busy utilzing your lower motor neurons and type Ia sensory afferents ;)
---
## γ motor neurons
<div style="font-size:0.7em; width:500px">
<div></div>
* γ motor neurons control the functional characteristics of the muscle spindles
* When muscles contract, spindle afferents do not fall silent. Instead γ neurons that terminate at spindle poles cause intrafusal fiber contraction at the poles, and lead to tension across the fiber in the presence of muscle contraction. This allows spindles to function at all muscle lengths and tensions
* Gain or γ bias refers to the fact that spindles can adjust how much output will happen when they are stretched. Large gain means a small amount of stretch applied to the intrafusal fibers will produce a large increase in the number of motor neurons recruited and an increase in firing rates. Gain is continually adjusted to meet circumstances
</div>
<div><img src="figs/Neuroscience5e-Fig-16.10-1R_copy_cc1a978.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.10</figcaption></div>
Note:
But the infrafusal muscle fibers are muscle-- why not just have the muscle spindle feedback and be done with it...
Need to adjust the muscle spindles so that they can provide useful feedbac across a range of muscle lengths.
Provide gain to keep muscle spindles active at all lengths.
Think about your big guns you use to hold that glass of oktoberfest... changing length of biceps
---
## γ motor neuron activity affects responses of muscle spindles
<figure><img src="figs/Neuroscience5e-Fig-16.11-0_copy_5d0c72d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.11</figcaption></figure>
Note:
---
## Stretch reflex video summary
<div><video height=400px controls src="figs/Animation16-01TheStretchReflex.mp4"></video><figcaption>Neuroscience 5e Animation 16.1</figcaption></div>
Note:
---
## Golgi tendon organs
<div style="font-size:0.7em; width:500px">
<div></div>
* Encapsulated afferent nerve endings located at the junction of the muscle and tendon
* Each tendon is innervated by a single sensory group Ib sensory axon
* Unlike spindle fibers, golgi tendon organs fire when muscle contracts
* Ib axons from Golgi tendon organs contact inhibitory local circuit neurons in the spinal cord (Ib inhibitory neurons) that synapse with the α motor neurons that innervate the same muscle
* Helps prevent fatigue
</div>
<div><img src="figs/Neuroscience5e-Fig-16.12-1R_5e5b3f0.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.12</figcaption></div>
Note:
* spindle system is feedback system to monitor and maintain muscle stretch
* Golgi tendon organ is feedback system to maintain muscle force
---
## Negative feedback regulation of muscle tension by Golgi tendon organs
<div style="width:400px">
<div></div>
* Negative feedback provided by by Golgi tendon organs
* When muscle contracts there is a feedback mechanism to prevent more contractions. Prevents damage and fatigue
</div>
<div><img src="figs/Neuroscience5e-Fig-16.13-0_5e4b9da.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.13</figcaption></div>
Note:
---
## Comparison of the function of muscle spindles and Golgi tendon organs
<figure><img src="figs/Neuroscience5e-Fig-16.12-2R_8559343.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.12</figcaption></figure>
Note:
---
## Comparison of the function of muscle spindles and Golgi tendon organs
<figure><img src="figs/Neuroscience5e-Fig-16.12-3R_bdafe5b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.12</figcaption></figure>
Note:
## Muscle reflexes: response to load and overload
<!-- <div><img src="figs/13-06_MuscleReflexes_L_8cefd3d.jpg" height="100px"><figcaption></figcaption></div> -->
---
## Flexion reflex pathways
* Reflexes that compensate posture when we withdraw from pain
* Involves several synaptic links
* Excitation of nociceptor leads to ipsilateral and contralateral responses
* Flexion reflex– stimulation of cutaneous receptors in the foot leads to activation of spinal cord local circuits that both withdrawal stimulated side and extend other side to provide compensatory support
Note:
CPG interneurons Type Axon projection in embryonic cord
V0 Commissural Rostrally
V1 Inhibitory (Renshaw cells and Ia interneurons) Rostrally and ipsilaterally
V2 Glutamatergic V2a and Inhibitory V2b Ipsilaterally and caudally
V3 Excitatory Commissural Caudally
Goulding M (July 2009). "Circuits controlling vertebrate locomotion: moving in a new direction". Nature Reviews. Neuroscience. 10 (7): 507–18. doi:10.1038/nrn2608. PMC 2847453free to read. PMID 19543221.
---
## Spinal cord circuitry responsible for the flexion reflex
<figure><img src="figs/Neuroscience5e-Fig-16.14-0_35309c0.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.14</figcaption></figure>
Note:
---
## Flexion reflex video summary
<div><video height=400px controls src="figs/Animation16-02TheFlexionReflex.mp4"></video><figcaption>Neuroscience 5e Animation 16.2</figcaption></div>
Note:
---
## Locomotion– an essential feature of animal life
<div style="font-size:0.8em;">
<div></div>
* Locomotion is a stereotyped action involving repetitions of the same movement
* Locomotion– a single limb can be thought of having two phases, a stance phase (limb is extended and in contact with the ground) and a swing phase (limb is flexed to leave the ground and then brought forward to begin next stance phase)
* Increases of speed reduce the amount of time it takes to complete the cycle. Stance phase gets quicker, swing phase stays relatively constant
* For quadrupeds, changes in speed are also accompanied by changes in the order of steps taken. At low speeds, back to front occurs first on one side then on the other. At a trot, right forelimb and left hindlimb are synchronized. At high speeds, two front limbs are synchronized as are the two hind limbs
* Pattern generators– once initiated by upper motor pathways or sensory input, pattern generators can keep locomotion going quite well until there is a signal to get out
</div>
Note:
* Flexion describes a bending movement that decreases the angle between a segment and its proximal segment
* Extension describing a straightening movement that increases the angle between body parts
* Abduction refers to a motion that pulls a structure or part away from the midline of the body
* Adduction refers to a motion that pulls a structure or part toward the midline of the body
---
## Central pattern generators organize the cycle of locomotion for terrestrial mammals
<figure><img src="figs/Neuroscience5e-Fig-16.15-0_312da6c.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 16.15</figcaption></figure>
Note:
* Defects in spinal cord connectivity interrupt pattern generation
* [cell article](http://www.cell.com/action/doSearch?searchType=quick&searchText=locomotion+eph&occurrences=all&journalCode=&searchScope=fullSite&contentType=video&startPage=)
* activating the mesencephalic locomotor region can trigger locomtion and change speed of movement by amount of input to spinal cord. Transection at thoracic level will still allow for coordinated locomotor movements. But not just a stretch reflex, due to CPGs present for each limb. These are all connected together in spanning circuits. Transection not allow for good walking in humans though-- maybe bipedalism requires more upper motor neuron control because of greater postural control requirements...
---
## Central pattern generators organize the cycle of locomotion for terrestrial mammals
<div><iframe src="https://www.youtube.com/embed/wPiLLplofYw" width="420" height="315"></iframe><figcaption>Locomotion in decerebrate cat</figcaption></div>
---
## Central pattern generator model circuit
<figure>
<figcaption>Interlimb coupling (C) with mutually inhibitory connections.
E, extensor. F, flexor. Arrows, excitatory. Closed circles, inhibitory
</figcaption>
<img src="figs/Ting-JNeurophys1998-Fig8_7b01f81.jpg" height="400px">
<figcaption>Ting et al., *J Neurophysiol* 1998, Fig. 8</figcaption></figure>
<!-- <figure><img src="figs/cpg-model-circuit_ce4156c.png" height="400px"><figcaption></figcaption></figure> -->
Note:
simple network of neurons that could result in alternating flexor and extensor muscle movements for locomotion and be basis of a central pattern generator circuit.
spinal locomotor and brainstem respiratory CPGs (Yuste et al, Nat Rev Neurosci 2005)
: have an 'excitatory core' of mutually excitatory interneurons
: ea. hemisegment of the spinal cord has this a core
: reciprocal inhibition between contralateral hemisegments results in alternating left–right motor output
---

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