293 lines
13 KiB
Org Mode
293 lines
13 KiB
Org Mode
# Instructions for org mode export
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# - to get export options: ctrl-c ctrl-e
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# - to export as latex pdf: ctrl-c ctrl-e l p
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#+OPTIONS: ':nil *:nil -:t ::t <:t H:3 \n:nil ^:t arch:headline
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#+OPTIONS: author:nil broken-links:nil c:nil creator:nil
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#+OPTIONS: timestamp:t title:nil toc:nil todo:nil |:t
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#+TITLE: Nils Koch
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#+DATE: <2021-08-16 Mon>
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#+EMAIL: nils.koch@mail.mcgill.ca
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#+TAGS: noexport(n)
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#+LATEX_CLASS: article
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#+LATEX_CLASS_OPTIONS: [letterpaper,10pt]
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#+LATEX_HEADER: \usepackage[margin=0.6in]{geometry}
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#+LATEX_HEADER: \usepackage{academicons}
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#+LATEX_HEADER: \usepackage{hyperref}
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#+LATEX_HEADER: \def\refname{\large References}
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#+LATEX_HEADER: \newcommand{\Pref}[1]{[P\ref{it:#1}]}
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#+LATEX_HEADER: \usepackage{academicons}
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#+LATEX_HEADER: \usepackage[breaklinks=true]{hyperref}
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#+LATEX_HEADER: \usepackage{graphicx}
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#+LATEX_HEADER: \usepackage{graphbox}
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#+LATEX_HEADER: \usepackage{matlab-prettifier}
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#+LATEX_HEADER: \usepackage[scaled]{helvet} \renewcommand\familydefault{\sfdefault}
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#+LATEX_HEADER: \graphicspath{{./Figures/}}
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#+LATEX_HEADER_EXTRA:
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# For citation colors
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#+LATEX_HEADER_EXTRA: \hypersetup{
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#+LATEX_HEADER_EXTRA: urlcolor={black!70}
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#+LATEX_HEADER_EXTRA: }
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#+DESCRIPTION:
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#+KEYWORDS:
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#+subtitle:
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#+LATEX_COMPILER: pdflatex
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#+BEGIN_EXPORT latex
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\renewcommand{\maketitle}
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\maketitle{
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\begin{center}
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\Huge \textbf{Update on Figures}}}\\
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\end{center}
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}
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%\thispagestyle{empty} %remove header on first page
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\titleformat{\section}{\Large\bfseries}{\thesection}{0pt}{}
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\titleformat{\subsection}{\large\bfseries}{\thesection}{0pt}{}
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\pagestyle{fancy}
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\fancyhf{}
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\renewcommand{\headrulewidth}{0pt} % remove lines as well
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\renewcommand{\footrulewidth}{0pt} % remove lines as well
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%\lfoot{\textcolor{black!50}{\footnotesize \today}}
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%\cfoot{\textcolor{black!50}{\footnotesize Nils Koch }}
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\rfoot{\textcolor{black!50}{\thepage}}
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%\lhead{}
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\chead{\today}
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%\rhead{}
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\newcommand{\squishlist}{
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\begin{list}{$\bullet$}
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{ \setlength{\itemsep}{0pt} \setlength{\parsep}{3pt} \setlength{\topsep}{3pt} \setlength{\partopsep}{0pt}
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\setlength{\leftmargin}{1.5em} \setlength{\labelwidth}{1em} \setlength{\labelsep}{0.5em} } }
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\newcommand{\squishend}{\end{list} }
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#+END_EXPORT
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* Firing Characterization:
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** Question figure addresses:
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Firing is a complicated phenomenon. How can it be simply characterized to compare the
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effects of changes in current properties?
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** Method by which data is generated:
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Schematic diagram that does not contain underlying data - contains different square
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root functions.
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** Conclusion from Figure:
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Firing can be characterized by the rheobase and the AUC (proprotional to the increase in
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firing after the rheobase). The rheobase and firing in a small range above it (AUC) are
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likely important for determining network excitability (I think this makes sense,
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would need references to support this).
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=10cm]{firing_characterization.pdf}
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\caption{A. Demonstrates AUC in cyan. B. Demonstrates what combinations of increased and
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decreased rheobase and AUC look like in terms of fI curves.}
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\label{fig:firing_charact}
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\end{figure}
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#+END_EXPORT
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* Diversity in Model Firing:
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We have used a number of neuronal models that do not burst to look at the effects
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of changes in current properties in firing given different cell types/current
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environments
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** Question figure addresses:
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Which model is used?
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** Rationale:
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The effect of a change in a current property cannot be assessed in only one cell
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type to understand the general effects of this change and to assess whether differences
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occur across cell types.
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** Method by which data is generated:
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Models from different sources are used and an example spike train is shown for each model
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along with a fI curve. The black dot on the fI curve indicates where the spike train is
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taken from and the green and red dots indicate the current at which the first and last
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spike occurs from an increasing and decreasing current ramp respectively. (These ramps
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can be seen in the ramp figure at the end).
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** Conclusion from Figure:
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The models use are diverse and display a variety of spike shapes, firing behaviours, and
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fI curve shapes.
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=18cm]{diversity_in_firing.pdf}
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\caption{Spike trains and corresponding fI curves from: A. Cb stellate, B. RS Inhibitory,
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C. FS, D. RS Pyramidal, E. RS Inhibitory +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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F. Cb stellate +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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G. FS +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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H. RS Pyramidal +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\), I. STN +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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J.Cb stellate \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) , K. STN \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\), L. STN,
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where +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) indicates the addition of Kv1.1 to the model
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and \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) indicates the exchange of the A type K+ current for Kv1.1. The black
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dot on the fI curve indicates where the spike train is taken from and the green and red
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dots indicate the current at which the first and last spike occurs from an increasing and
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decreasing current ramp respectively.}
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\label{fig:div_firing}
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\end{figure}
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#+END_EXPORT
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* IB model issue: :noexport:
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** Issue Background:
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IB (intrinsicially bursting) model from Pospischil et al. 2008 uses a leak conductance
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of 0.1. This results in bursting like firing initially (see bottom right of Figure
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\ref{fig:IB}) and requires large currents to be injected (> 0.75 nA). When the Kv1.1
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current is added to this model (bottom right Figure \ref{fig:IB}) the bursting
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behaviour is diminished but the currents needed to get firing are still high. As a
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result I decreased the leak conductance by a factor of 10 to 0.01 as seen in the
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upper right of Figure \ref{fig:IB}. This is the model that I used for the sensitivity
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analysis and modelling of Kv1.1 mutations. However, when the original IB model has a
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reduced leak current (of 0.01) it bursts and only for a small current range (see upper
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left of Figure \ref{fig:IB}).
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** Issue:
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Which model to use? To use the model with reduced leak that has nice properties with
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Kv1.1 added, the bursting and weird fI curve of the model without Kv1.1 needs to be
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addressed (bursting is not well captured by the analysis methods). To use the model with
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the large leak current (the original model), the large input currents is concerning and
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the sensitivity analysis and Kv1.1 mutation modelling would need to be re-done for this
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model with and without Kv1.1 (with 20/24 cores on the Kraken this would take 2-3 days
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I think). Alternatively, as neither option really sits well with me, we could remove this
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model from all figure and discussion and focus on the other models that in their
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original states (and with Kv1.1 added) have repetitive firing without bursting.
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=15cm]{IB_issue_plot.pdf}
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\caption{The fI curves and exampling spike trains from the IB model with different
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Leak conductances without and with (+Kv1.1) Kv1.1 conductance.}
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\label{fig:IB}
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\end{figure}
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#+END_EXPORT
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* Rheobase Sensitivity Analysis:
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I am not yet happy with this figure's layout
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** Question figure addresses:
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How is rheobase affected by changes in current properties across models? Is the change
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in rheobase always in the same direction across models?
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** Method by which data is generated:
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A one factor at a time (OFAT) sensitivity analysis was performed on the currents common
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to all or most models, where one current property was changed systematically at a time,
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the firing responses simulated and the fI curves computed. From this fI curve the
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largest injected current at which no firing occurs and the smallest injected
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current at which firing occurs were obtained. This current interval was then simulated
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to obtain the rheobase at greater resolution.
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** Conclusion from Figure:
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Generally the effect on rheobase is similar across all models/current environments
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=18cm]{rheobase_correlation.pdf}
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\caption{}
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\label{fig:rheo}
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\end{figure}
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#+END_EXPORT
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* AUC Sensitivity Analysis:
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I prefer the first layout
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** Question figure addresses:
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How is AUC affected by changes in current properties across models? Is the change
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in AUC rheobase always in the same direction across models?
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** Method by which data is generated:
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A one factor at a time (OFAT) sensitivity analysis was performed on the currents common
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to all or most models, where one current property was changed systematically at a time,
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the firing responses simulated and the steady-state fI curves computed. From this fI
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curve the largest injected current at which no firing occurs was obtained and the
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integral from this current using the composite trapezoidal rule for 1/5 of the current
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range.
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** Conclusion from Figure:
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A given current property change does not necessarily cause the same
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change in rheobase and as such the outcome of a given change is dependent on the
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current environment or cell type.
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=18cm]{AUC_correlation.pdf}
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\caption{}
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\label{fig:AUC}
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\end{figure}
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#+END_EXPORT
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* Kv1.1 mutation simulation:
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** Question figure addresses:
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Do mutations of Kv1.1 cause similar effects on firing across cell types or is the effect
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cell type (and thus neuronal network) dependent?
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** Method by which data is generated:
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Published Kv1.1 mutations (Lauxmann et al 2021) are simulated in all models containing
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Kv1.1 or an inactivating K^+ current by altering the current properties according to
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those experimentally measured for each mutation. The firing of each model for each
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mutation are then simulated and the rheobase and AUC are computed.
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** Conclusion from Figure:
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The effects of Kv1.1 mutations on rheobase are highly correlated across models indicating
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that these mutations affect the rheobase in a similar fashion. However, the effect of
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Kv1.1 mutations vary across models as seen by the different correlation magnitudes
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between models. Thus although these mutations affect rheobase in a similar manner, the
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effect on AUC cannot easily be generalized and depends on cell type.
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Furthermore, this Figure demonstrates why characterization of mutations in terms of
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LOF or GOF in relation to firing overlooks potentially important characteristics of
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the changes in firing seen in different cell types. Thus, the characterization LOF
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and GOF is useful at a channel level to characterize the effects of a mutation on
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the current, but cannot and should not be blindly extended to characterize the
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effects of the mutation on firing as LOF and GOF, not only because the current
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environment in which this mutation occurs is a key determinant of the firing outcome,
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but also that firing is complex and not easily characterized as LOF or GOF.
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=18cm]{simulation_model_comparison.pdf}
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\caption{}
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\label{fig:kv11}
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\end{figure}
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#+END_EXPORT
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* Ramp Firing - For Supplements?:
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** Question figure addresses:
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How does the firing of the models look like with a ramp protocol?
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** Method by which data is generated:
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A 4 second ramp with the same current range as the step currents used to obtain fI
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plots is used and the firing of all models is simulated. The resulting spike trains
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are plotted.
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** Conclusion from Figure:
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The diversity of firing seen with step currents is also seen with current ramps. The
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ramps highlight the hysteresis in models.
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#+BEGIN_EXPORT latex
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\begin{figure}[H]
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\includegraphics[align=c,width=20cm]{ramp_firing.pdf}
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\caption{A. Cb stellate, B. RS Inhibitory,
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C. FS, D. RS Pyramidal, E. RS Inhibitory +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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F. Cb stellate +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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G. FS +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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H. RS Pyramidal +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\), I. STN +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\),
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J.Cb stellate \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) , K. STN \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\), L. STN,
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where +\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) indicates the addition of Kv1.1 to the model
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and \(\Delta\)\(\mathrm{K}_{\mathrm{V}}\mathrm{1.1}\) indicates the exchange of the A type K+
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current for Kv1.1.}
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\label{fig:ramp}
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\end{figure}
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#+END_EXPORT
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