Origin of heterogeneous spiking patterns in spinal dorsal horn neurons (Balachandar & Prescott 2018)

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Accession:256628
"Neurons are often classified by spiking pattern. Yet, some neurons exhibit distinct patterns under subtly different test conditions, which suggests that they operate near an abrupt transition, or bifurcation. A set of such neurons may exhibit heterogeneous spiking patterns not because of qualitative differences in which ion channels they express, but rather because quantitative differences in expression levels cause neurons to operate on opposite sides of a bifurcation. Neurons in the spinal dorsal horn, for example, respond to somatic current injection with patterns that include tonic, single, gap, delayed and reluctant spiking. It is unclear whether these patterns reflect five cell populations (defined by distinct ion channel expression patterns), heterogeneity within a single population, or some combination thereof. We reproduced all five spiking patterns in a computational model by varying the densities of a low-threshold (KV1-type) potassium conductance and an inactivating (A-type) potassium conductance and found that single, gap, delayed and reluctant spiking arise when the joint probability distribution of those channel densities spans two intersecting bifurcations that divide the parameter space into quadrants, each associated with a different spiking pattern. ... "
Reference:
1 . Balachandar A, Prescott SA (2018) Origin of heterogeneous spiking patterns from continuously distributed ion channel densities: a computational study in spinal dorsal horn neurons. J Physiol 596:1681-1697 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type:
Brain Region(s)/Organism:
Cell Type(s): Abstract Morris-Lecar neuron; Dorsal Root Ganglion (DRG) cell;
Channel(s): I Na,t; I K; I A; I Potassium;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s):
Simulation Environment: MATLAB;
Model Concept(s): Bifurcation; Activity Patterns; Parameter Fitting; Action Potential Initiation; Action Potentials; Parameter sensitivity;
Implementer(s):
Search NeuronDB for information about:  I Na,t; I A; I K; I Potassium;
%Arjun Balachandar 2016
%fit_bivariate.m
%Algorithm that fits a Bivariate Normal Distribution (BND) to match
%observed proportions of neurons of each firing-type (i.e. percentage of
%observed neurons whose firing-pattern (FP) belongs to a given FP region)
%The observed proportions can be genrated by a 'target' BND, which the
%algorithm then attempts to re-create, or from inputted values of
%proportions in each region
%(Note: this code does not fit sigma (std-dev) of the distributions, instead done
%in fit_bivariate_sigma)
%See methods for details.

%***USER MODIFIABLE- refers to variables to be changed by user****

clc;
clear all;

bivargauss = @bivariable_gaussian; %used to generate BND equation

match_bivar = 1; %if 1, set target_volume to volume calculated from trial distribution, see if algorithm recreates this

loadVariables = 1;

%Data-file (generated from AutoSim.m) used to create slice that is used for fitting
load('AutoSim_istim060_distim10_ioff20_dgA0_maxgsub15'); %Data containing i_stim=60, i_off=0, 15x15 grid-size of gA vs. gsub


%size of grid (i.e. size of slice) used by algorithm - INPUT BY USER
grid_size = 10;
xmax = grid_size;
xmin = 0;
ymax = grid_size;
ymin = 0;

if num_istim > 1 %if many i_stim in the data-file, use value = inputted-by-user
    value = 60;
else
    value = max_istim; %if only one stimulation level, use that (i_stim = max_istim)
end
ind = 1;


target_volume = zeros(5);
%target_volumes = [R, SS, DO, GAP, RF] is the order of output of the firing-pattern type
target_volume = target_volume(:);
numRegions = length(target_volume);

x0 = (xmax-xmin)/2; y0 = (ymax-ymin)/2;
muX = x0; muY = y0;
mu = [muX; muY];
sigma_x = 1;
sigma_y = 1;

%***USER INPUT***
%The user inouts 'target' values of the BND, which the algorithm will try
%to determine simply from knowing the proportions of neurons in each
%FP-region that the target BND calculates.
if match_bivar == 1
    p_match = -0.6; %rho (correlation coefficient, i.e. rotation) of the distribution
    muX_match = 3; %centre (i.e. average) of the distribution
    muY_match = 4;
    sigma_x_match = 1;%sigma_x;
    sigma_y_match = 1;%sigma_y;
end

del = 0.1;
dx = del;
dy = del;

num_xTot = (max_gsub-min_gsub)/dx + 1; %for modified domain size
num_x = (xmax-xmin)/dx + 1;
num_y = (ymax-ymin)/dy + 1;
x_domain = linspace(xmin,xmax,num_x);
y_domain = linspace(ymin,ymax,num_y);

[X, Y] = meshgrid(xmin:dx:xmax, ymin:dy:ymax);

FP_domain = zeros(num_x,num_y);

%create slice (of specified specified domain size 'grid_size')
cur_ind = 1;
slice_size = num_x*num_y;
param_array_slice = zeros(slice_size, 6 + nSpikeATPs);
for i=1:(num_istim)*(num_x)*(num_y)
    if param_array(i,ind) == value
        for j=1:(6+nSpikeATPs)
            param_array_slice(cur_ind,j) = param_array(i,j);
        end
        cur_ind = cur_ind + 1;
    end
end
for i=0:num_x-1
    for j=0:num_y-1
        FP_domain(j+1,i+1) = param_array_slice(j*num_xTot + i + 1,4);
    end
end



integ = @trap_integ; %function to calculate area in a given region, by calculating double-integral using trapezoid method

%Centroid (centre of mass of each region) - calculated as shown below:
centroids = zeros(numRegions,2); 
numPoints = zeros(numRegions);
for i=0:num_x-1
    for j=0:num_y-1
        next_point = FP_domain(i+1,j+1) + 1;
        centroids(next_point,1) = centroids(next_point,1) + i*dx;
        centroids(next_point,2) = centroids(next_point,2) + j*dy;
        numPoints(next_point) = numPoints(next_point) + 1;
    end
end
for i=1:numRegions
    centroids(i,1) = centroids(i,1)/numPoints(i);
    centroids(i,2) = centroids(i,2)/numPoints(i);
end


error_thres = 0.001; %if algorithm calculates poportions that are within error_thres of the observed proportions of the target BND, stop algorith and return optimized parameters
error = 1;
curAveComplete = 1;
dp = 0.1;
p_mini = -0.9; %initially, rho/p is varied in increments of 0.1 from -0.9 to 0.9 
p_max = abs(p_mini);
p_init = p_mini;
p = p_init;
p_min = p;
min_error = 20;

%After algorithm gets within error less than error_changetoAccu, algorithm
%changes rho/p by finer increments (0.01< from -0.99 to 0.99.
error_changeToAccu = 0.003;
p_mini_accu = -0.99;
p_max_accu = abs(p_mini_accu);
p_init_accu = p_mini_accu;
dp_accu = 0.01;

volumes = zeros(numRegions);
volumes = volumes(:);
min_volumes = zeros(numRegions);
min_volumes = min_volumes(:);
min_volumes_prev = zeros(numRegions,1);
min_volumes_prev = min_volumes_prev(:);

%after each iteration, store error (i.e. MaxError), used to show how error decreases
%over iterations:
errors = zeros(1000);
uX = zeros(1000);
uY = zeros(1000);
ps = zeros(1000);
errors = errors(:);
uX = uX(:);
uY = uY(:);
ps = ps(:);

iters = zeros(1000);
iters = iters(:);
iter = 0;

if match_bivar == 1
    volumes_match = zeros(numRegions); %volumes under target distribution
    
    fun_match = bivargauss(p_match,muX_match,muY_match,sigma_x_match,sigma_y_match);
    volumes_match = integ(fun_match,x_domain,y_domain,FP_domain);
    
    target_volume = volumes_match; %set target volume to this distributions volumes
    display(target_volume);
    
    %display target distribution
    Z = fun_match(X,Y);
    figure('name','Target Bivariate-fit Contour Plot');
    [hC hC] = contourf(X,Y,Z,1000);
    set(hC,'LineStyle','none');
    xlabel('gsub');
    ylabel('gA');
    title(['target vol=',mat2str(target_volume),' p_tar=',num2str(p_match)]);
end

%See methods for details
while error~=0
    %Step 1: vary rho given current uX and uY (centre of BND)
    while curAveComplete~=0 | error~=0
        if min_error<error_changeToAccu & p_init~=p_init_accu %conditions after which algorithm proceeds with more fine increments in rho, to fine-tune optimization
            p_init = p_init_accu;
            p_max = p_max_accu;
            p_mini = p_mini_accu;
            dp = dp_accu;
        end
        fun = bivargauss(p,muX,muY,sigma_x,sigma_y);
        volumes = integ(fun,x_domain,y_domain,FP_domain);
        diff = target_volume - volumes;
        max_diff = max(abs(diff)); %i.e. MaxError (maximum error in the proportions (max difference between calculated and target proportions))
        if max_diff<error_thres %if algorithm has reached target error_thres, break and return optimized parameters
            min_error = max_diff;
            p_min = p;
            min_volumes = volumes;
            error = 0;
            curAveComplete = 0;
            break;
        else
            if p < p_max %vary rho to find optimal value
                if min_error > max_diff %set new minimum error
                    min_error = max_diff;
                    p_min = p;
                    min_volumes = volumes;
                end
                p = p + dp;
            else
                curAveComplete = 0;
                display(min_volumes);
                break;
            end
        end
    end
    
    display(p_min);
    display([p_init; dp]);
    
    muX_prev = muX; muY_prev = muY;
    muX_new = muX;
    muY_new = muY;
    diff = target_volume - min_volumes;
    
    %Step 2: If after varying rho for given uX and uY, error still not
    %small enough, then move centre using centroids to calculate direction
    %vectors, which are scaled by the magnitude of error in each FP region
    %(hence move in large steps towards/from areas of large negative/positive
    %difference in calc and target proportions, and move in smaller steps
    %for regions where error is smaller).
    if error~=0
        %keep track of MaxError each iteration
        errors(iter+1) = max(abs(diff));
        uX(iter+1) = muX_new;
        uY(iter+1) = muY_new;
        ps(iter+1) = p_min;
        iters(iter+1) = iter;
        display(max(abs(diff)));
        display(iter);
        iter = iter + 1;
        
        mu = [muX; muY];
        for i=1:numRegions
            ci = [centroids(i,1); centroids(i,2)];
            muX_new = muX_new + ((centroids(i,1)-muX)/norm(ci-mu))*diff(i);
            muY_new = muY_new + ((centroids(i,2)-muY)/norm(ci-mu))*diff(i);
        end
        muX = muX_new; muY = muY_new;
        mu = [muX; muY];
        display(mu);
        p = p_init;
        if abs(muX-muX_prev)<=0.001 & abs(muY-muY_prev)<=0.001
            if p_init~=p_init_accu
                p_init = p_init_accu;
                p_max = p_max_accu;
                p_mini = p_mini_accu;
                dp = dp_accu;
            else
                error = 0;
                break;
            end
        elseif max(abs(min_volumes_prev-min_volumes))<=0.001
            if p_init~=p_init_accu
                p_init = p_init_accu;
                p_max = p_max_accu;
                p_mini = p_mini_accu;
                dp = dp_accu;
            else
                error = 0;
                break;
            end
        end
        
        min_volumes_prev = min_volumes;
    else
        break;
    end
end

%***Display optimized parameters and plot of calculated BND***
display(min_volumes);
display(p_min);
display(mu);
fun_min = bivargauss(p_min,muX,muY,sigma_x,sigma_y);
Z = fun_min(X,Y);

figure('name','Bivariate-fit Contour Plot');
[hC hC] = contourf(X,Y,Z,1000);
set(hC,'LineStyle','none');
xlabel('gsub');
ylabel('gA');
title(['max error = ',num2str(max(abs(diff))),'; target vol=',mat2str(target_volume),' p_tar=',num2str(p_match),' mux_tar=',num2str(muX_match),' muy_tar=',num2str(muY_match),'; p_calc=',num2str(p_min),' mux_calc=',num2str(muX),' muy_calc=',num2str(muY),' calc vol=',mat2str(min_volumes)]);
%,'; calc vol=',mat2str(min_volumes)

%%%%%%%%%%%%%%%%%%
%Plot FP-slice
% if loadVariables == 1
%     x_size = num_x;
%     y_size = num_y;
%     gA_axis = linspace(ymin,ymax,num_y);
%     gsub_axis = linspace(xmin,xmax,num_x);
%     figure('name','Contour Plot Slice - Firing Pattern');
%     [aC aC] = contourf(FP_domain.',5);
%     title(['istim = ',int2str(value),', ioff = ',int2str(i_off)]);
%     xlabel('gsub');
%     ylabel('gA');
%     set(aC,'LineStyle','none');
%     set(gca, 'XTick', 1:x_size); % Change x-axis ticks
%     set(gca, 'XTickLabel', gsub_axis); % Change x-axis ticks labels.
%     set(gca, 'YTick', 1:y_size); % Change x-axis ticks
%     set(gca, 'YTickLabel', gA_axis); % Change x-axis ticks labels.
% end


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