Computational steps towards unwrapping the role of myelin in - - PowerPoint PPT Presentation

▶
computational steps towards unwrapping the role of myelin
SMART_READER_LITE
LIVE PREVIEW

Computational steps towards unwrapping the role of myelin in - - PowerPoint PPT Presentation

Sep 17, 2022 480 likes •1.09k views

Computational steps towards unwrapping the role of myelin in olfactory signal processing Justjn Losacco, Daniel Ramirez-Gordillo, Jessie Gilmer Elizabeth A. Gould, Nicolas Busquet, Douglas Shepherd, Robert Dietz, Paco Herson, Fabio M. Simoes de

slide-1
SLIDE 1

Computational steps towards unwrapping the role of myelin in olfactory signal processing

Justjn Losacco, Daniel Ramirez-Gordillo, Jessie Gilmer Elizabeth A. Gould, Nicolas Busquet, Douglas Shepherd, Robert Dietz, Paco Herson, Fabio M. Simoes de Souza, Anan Li, Nicholas M. George, Wendy B. Macklin

slide-2
SLIDE 2

Ramón y Cajal

slide-3
SLIDE 3

Computational steps towards unwrapping the role

  • f myelin in olfactory signal processing
  • Oscillatjons are augmented and dimensionality changes

as the animal learns to difgerentjate odorants in the go- no go task

  • Mild Myelin Disruptjon Elicits Early Alteratjon in

Olfactory Behavior and Proliferatjon in the Subventricular Zone

slide-4
SLIDE 4

Optetrode

0.22 NA

slide-5
SLIDE 5

Go-no Go Associatjve Learning Task

slide-6
SLIDE 6

PAC caclulatjon: Tort et al. J. Neurophys. 104:1195, 2010

slide-7
SLIDE 7
slide-8
SLIDE 8

Li and Cleland. PLOS Comp. Biol. 13:e1005760, 2017

slide-9
SLIDE 9

Granule cell inhibition gives rise to gamma frequency oscillations, and these

  • scillations are augmented by gap junctions between mitral cells

Pouille et al J. Physiol. 595:5965, 2017

slide-10
SLIDE 10

PAC calculatjon: Tort et al. J. Neurophys. 104:1195, 2010

Estjmatjng Phase Amplitude Coupling (PAC)

slide-11
SLIDE 11

PAC for a profjcient mouse

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-12
SLIDE 12

Peak angle variance decreases for S+ and increases for S- as the mouse learns

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-13
SLIDE 13

What happens if the downstream observer of gamma power uses a window at the peak or trough of the theta oscillatjon?

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-14
SLIDE 14

What happens if the downstream observer of gamma power uses a window at the peak or trough of the theta oscillatjon?

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-15
SLIDE 15

Decoding of odorant identjty with linear discriminant analysis using the theta peak- referenced gamma power preforms betuer than trough-referenced gamma power

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-16
SLIDE 16

Decision tjme is the same for theta peak-referenced wavelet power linear discriminant analysis and for lick divergence

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-17
SLIDE 17

Example of principal component separatjon as the animal learns to difgerentjate the odorants

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-18
SLIDE 18

What is the dimensionality of the peak-referenced gamma power?

Litwin-Kumar et al., 2017, Neuron 93, 1153–1164

slide-19
SLIDE 19

Dimensionality of the peak-phase referenced gamma power difgers between locatjons and changes afuer learning

  • Confjdentjal. Losacco, Ramirez-Grodillo et al, manuscript in preparatjon
slide-20
SLIDE 20

Conclusions

  • Theta peak-referenced gamma power carries

information on odor identity

  • Theta trough-referenced gamma power carries

significantly less information on odor identity

  • As the mouse learns to differentiate the odorant

the dimensionality of theta-peak referenced gamma power decreases

slide-21
SLIDE 21

Computational steps towards unwrapping the role

  • f myelin in olfactory signal processing
  • Oscillatjons are augmented and dimensionality changes

as the animal learns to difgerentjate odorants in the go- no go task

  • Mild Myelin Disruptjon Elicits Early Alteratjon in

Olfactory Behavior and Proliferatjon in the Subventricular Zone

slide-22
SLIDE 22

Neurological problems in mild myelin disruption (early Multiple Sclerosis): Y

  • ung adult PLP knockout mouse

htup://www.nih.gov Myelin is key for neuronal transmission of informatjon

PLP

Proteolipid protein (PLP) is a structural component of the myelin sheath Gould et. al. eLife e34783, 2018

slide-23
SLIDE 23

Plp point mutatjons or gene duplicatjons lead to the dysmyelinatjng diseases, Pelizaeus-Merzbacher disease (PMD) and spastjc paraplegia type 2

10 years old, Jacob Trossman, htup://jacobsladder.ca/pmd/

slide-24
SLIDE 24

Deletion of plp1 leads to loss of myelin compaction

Wild type (WT) Plp1 deletjon (Plp-null)

Klugmann, M, et al (1997) Neuron Rosenbluth, J, et al (2009) Journal of Neuroscience Research

slide-25
SLIDE 25

3 month PLP-null overstep rear paw

p<0.01, repeated measures ANOVA Gould et. al. eLife e34783, 2018 Gould et. al. eLife e34783, 2018

slide-26
SLIDE 26

Problems with motor coordination: swimming

WT Plp-null

Gould et. al. eLife e34783, 2018

slide-27
SLIDE 27

Puzzle box: comprehensive test of cognitive function

Entry to goal box Problem-solving Short-term memory Long-term memory Gould et. al. eLife e34783, 2018

slide-28
SLIDE 28

Cognitive function is impaired in PLP-null mice

Gould et. al. eLife e34783, 2018 Gould et. al. eLife e34783, 2018

slide-29
SLIDE 29

Plp1-null mice exhibit increased exploration

  • f novel social odors

Gould et. al. eLife e34783, 2018

slide-30
SLIDE 30

The distance traveled, velocity and behavioral outcome did not differ in a subset of behavioral tasks

Gould et. al. eLife e34783, 2018

slide-31
SLIDE 31

Region-wide analysis of oligodendrocytes (OL)

Early Progressive Late < 2 months > 16 months 2 -16 months Oligodendrocytes Demyelinatjon (spinal cord) Normal appearance Cellular

**Klugmann et al. (1997)

Are there region-specifjc difgerences?

PLP-eGFP labels majority of mature oligodendrocytes in adult mouse Established in 2002 by Mallon et al.

30 m sectjon tjled image 𝛎 WT PLP-null

slide-32
SLIDE 32

Clear tissue enables high volume imaging

Proteins Plasma membrane DNA Epp et al 2014

slide-33
SLIDE 33

Light sheet fluorescence microscopy

Power and Huisken (2017) Nature Methods

slide-34
SLIDE 34

Light sheet fluorescence microscopy

Power and Huisken (2017) Nature Methods

Co-planar requirement

slide-35
SLIDE 35

Heterogenous RI breaks co-planarity in light sheet fluorescence microscopy

Chung, K, et al (2013) Nature Yang, B, et al (2014) Cell Ryan, D. et al (2017) Nature Communications

slide-36
SLIDE 36

Heterogenous RI breaks co-planarity in light sheet fluorescence microscopy

Chung, K, et al (2013) Nature Yang, B, et al (2014) Cell Ryan, D. et al (2017) Nature Communications

slide-37
SLIDE 37

Inertia-free volumetric imaging

Dz

ETL-2 = -

1 MDO

2

n× fL1

2

fETL-2 é ë ê ù û ú

Fahrbach, F. et al (2013) Optics Express Mickoleit, M. et al (2014) Nature Methods Chmielewski, A. et al (2015) Scientific Reports Ryan, D. et al (2017) Nature Communications Patent issued April 8th 2018

Inertja free imaging

slide-38
SLIDE 38

Computer vision to maintain co- planarity

Ryan, D. et al (2017) Nature Communications

slide-39
SLIDE 39

Light sheet imaging oligodendrocytes in the olfactory bulb in PLP-GFP mice

Adaptjve light sheet microscopy of PLP-eGFP. Ryan et al. Nature Comms. 8:612, 2017

slide-40
SLIDE 40

Loss of plpl1 alters regional production of

  • ligodendrocyte cells

Gould, E. et al (2018) eLife

slide-41
SLIDE 41

Loss of plpl1 alters regional production of

  • ligodendrocyte cells

Gould, E. et al (2018) eLife

slide-42
SLIDE 42

Increase in OL is region-specific increase in the CC of the 6 month PLP- null mice

*

Genu Splenium

Gould et. al. eLife e34783, 2018

slide-43
SLIDE 43

Proliferative response in SVZ

* EDU/SOX2 EDU WT SVZ Null SVZ 4 month 3 mice/genotype

WT PLP-null

slide-44
SLIDE 44

Summary of EDU experiments:

Increase in OL in CC and OB of young adult PLP-null mice Accumulatjon of new OL

Local OPC- no change Subventricular zone (SVZ)- proliferatjon increased

Day 1 2 3 3 weeks EDU+ OL 4 hours Gould et. al. eLife e34783, 2018

slide-45
SLIDE 45

Cortjcal axon disruptjon in Plp-null mice evidenced by the presence of axonal spheroids

Gould et. al. eLife e34783, 2018

slide-46
SLIDE 46

Mild demyelination elicits a decrease in the velocity of action potential transmission in the corpus callosum

Gould et. al. eLife e34783, 2018

slide-47
SLIDE 47

Ramón y Cajal

slide-48
SLIDE 48

Modeling predicts that a decrease in axonal conduction velocity should increase neuronal

  • scillations in piriform cortex

Gould et. al. eLife e34783, 2018

slide-49
SLIDE 49

Optetrode

0.22 NA

slide-50
SLIDE 50

Go-no Go Associatjve Learning Task

slide-51
SLIDE 51

Synchronous neuronal activity in piriform cortex

Myelin disruptjon leads to ineffjcient conductjon Alters tjming within neuronal populatjons Alters oscillatjons

Rewarded Unrewarded

Impairs synchronous neuronal actjvity

Gould et. al. eLife e34783, 2018

slide-52
SLIDE 52

Oscillations in piriform cortex

9M Plp-null Rewarded Unrewarded Gould et. al. eLife e34783, 2018

slide-53
SLIDE 53

Myelin disruption can be a primary cause of altered oscillations

Mann-Whitney U test. Data not normally distributed Gould et. al. eLife e34783, 2018

slide-54
SLIDE 54

Gould et. al. eLife e34783, 2018 Wild type Plp-null

slide-55
SLIDE 55

In piriform cortex feedback inhibition shortens the response to the odorant ensuring correct decoding of odor identity

Bolding et al., Science 361, eaat6904 (2018)

slide-56
SLIDE 56

Odorant responses are severely diminished in the piriform cortex of Plp-null mice

  • Confjdentjal. Gould et. al. unpublished
slide-57
SLIDE 57

In collaboration with Fabio Simoes de Souza we intend to model the effect of demyelination on olfactory circuit function

  • Confjdentjal. Gould et. al. unpublished
slide-58
SLIDE 58

Hippocampal oscillatjons

In the young adult mouse mild myelin dysfunctjon leads to:

  • Select defjcits in higher-order processes (motor coordinatjon,

problem-solving, motjvatjon, sensory perceptjon)

  • Triggering of productjon of oligodendrocyte progenitors by the

subventricular zone

  • Transfer of new oligodendrocyte progenitors to the olfactory bulb

and the genu of the corpus callosum

  • Decreased actjon potentjal conductjon velocity
  • Increased oscillatjons

Mild myelin disruptjon

These fjndings raise the questjon whether the SVZ productjon of new oligodendrocytes and the accompanying increase in

  • scillatory power is a protectjve response that reduces the

behavioral efgects of the loss of PLP in myelin

slide-59
SLIDE 59

Cajal, Proc. R. Soc. Lond. 55, 444, 1894, also see Gire et. al. Neuron 78:416, 2013

Botuom line: In order to understand the brain it is key to questjon your (my) unconscious bias

Our CU neurophotonics group is hiring a postdoctoral fellow with interest in interactjng with engineers to beautjful Colorado!