Neuronal gain modulability is determined by dendritic morphology: A computational optogenetic study

“The existence 38 of both excitatory [26] and inhibitory opsins [27, 28] suggests the possibility of altering 39 the balance of excitatory and inhibitory currents locally in dendrites, to act as a 40 synthetic substitute for the effect of excitatory and inhibitory presynaptic input.”

“and stabilized step-function opsins (SSFO) [48] may be suitable, as they do not required 399 continuous illumination to be active, and have their suitability for loose control has 400 already been demonstrated when driven by inputs located at the soma [47].”

“Thus, in addition to the influence 308 of dendrites on firing patterns [24, 35] and their role in dendritic computation [36,37], 309 our results demonstrate a new aspect to dendrites that directly relates the 310 morphological properties of an individual neuron to its functional role within a network.”

“Thus, in addition to the influence 308 of dendrites on firing patterns [24, 35] and their role in dendritic computation [36,37], 309 our results demonstrate a new aspect to dendrites that directly relates the 310 morphological properties of an individual neuron to its functional role within a network.”

“354 Tracing studies have hinted that within pyramidal cells in sensory areas, there is 355 synaptic targetting with feedforward presynaptic input from the thalamus tends to 356 synapse onto basal dendrites, while input from higher cortical areas instead connects 357 within apical dendrites [34, 41].”

“There have been several proposed mechanisms for how a neuron alters 14 the relationship between its input and output, including the use of shunting inhibition to 15 shift the input-output curve [12, 13], and varying the rate of background synaptic noise, 16 decreasing the ability of the neuron to detect target input s…”

“There have been several proposed mechanisms for how a neuron alters 14 the relationship between its input and output, including the use of shunting inhibition to 15 shift the input-output curve [12, 13], and varying the rate of background synaptic noise, 16 decreasing the ability of the neuron to detect target input s…”

“397 For the general purpose of optogenetic gain control, step-function opsins (SFO) [47] 398”

“Neocortical neurons vary in modulability, with gain modulation having been observed in 6 cortical pyramidal cells from layers 2/3, 5 and 6 [9, 10], whereas input-output 7 relationships in some other cell types, such as entorhinal stellate cells, appear to be 8 much less modulable [11].”

“Its role in neuronal computation has been the subject of much investigation [1–4], and its dysfunction has been implicated in a range of disorders from attention deficit disorders, through to schizophrenia, autism and epilepsy [5–8].”

“The existence 38 of both excitatory [26] and inhibitory opsins [27, 28] suggests the possibility of altering 39 the balance of excitatory and inhibitory currents locally in dendrites, to act as a 40 synthetic substitute for the effect of excitatory and inhibitory presynaptic input.”

“Our model of a co-activated opsin utilizes our previously published 6-state models of channelrhodopsin-2 (ChR2) [43,50] and halorhodopsin (NpHR) [51] open state contributes to the generation of the photocurrent i photo for each opsin type, which is calculated per compartment and is additionally…”

“The TREES toolbox [53] 439 was used for steady-state analysis of injected current in abstract models, and 440 NeuroTools toolbox [54] was used for spiketrain analysis.”

“Tracing the voltage for each dendrite section from injection site to soma (black), as well as sister branches and other primary branches (grey), shows the attenuation also varies with dendritic morphology, and is consistent with previous studies [30]; (E) Spiking responses (shown in panel F) were calculated by driving…”

“neurons, the stratified output for illumination suggests that if net drive to the dendrite 330 is able to sufficiently cover the entire arbor, then L5PCs will be gain-modulable 331 independent of the location of the driving input, which has been shown to govern the 332 input-output relationship for single inputs [18,…”

“between number of distinct sites that can be targeted and the frequency of their 347 stimulation [40].”

“(A) Layer 5 pyramidal cell, taken from [31]; (B) (top) Soma membrane voltage for the resulting net photocurrent as xNpHR is increased for irradiance=1mW/mm2 before current injection.”

“Neocortical neurons vary in modulability, with gain modulation having been observed in 6 cortical pyramidal cells from layers 2/3, 5 and 6 [9, 10], whereas input-output 7 relationships in some other cell types, such as entorhinal stellate cells, appear to be 8 much less modulable [11].”

“We used a Layer II hippocampal stellate cell model 185 previously published by [32], based on reconstructions from [33].”

“There have been several proposed mechanisms for how a neuron alters 14 the relationship between its input and output, including the use of shunting inhibition to 15 shift the input-output curve [12, 13], and varying the rate of background synaptic noise, 16 decreasing the ability of the neuron to detect target input s…”

“383 Optogenetic illumination protocols in current use can generally be classified as “hard 384 control”, in which the output of a cell is written directly by using high levels of 385 illumination to induce either spiking or hyperpolarization [45,46].”

“A subsequent 17 theoretical study posits that both mechanisms may be necessary [16], which is supported 18 by experimental evidence from intracellular in vivo recordings [17], indicating that these 19 processes are not mutually exclusive and may instead operate in different regimes.”

“82 The contribution of branching has been investigated previously, and found to 83 attenuate both voltage signals [30] and membrane resistance [20].”

“Each of the abstract neuron models we created included a soma and approximately 125 dendritic sections that were arranged with varying degrees of branching.”

“neurons, the stratified output for illumination suggests that if net drive to the dendrite 330 is able to sufficiently cover the entire arbor, then L5PCs will be gain-modulable 331 independent of the location of the driving input, which has been shown to govern the 332 input-output relationship for single inputs [18,…”

“The existence 38 of both excitatory [26] and inhibitory opsins [27, 28] suggests the possibility of altering 39 the balance of excitatory and inhibitory currents locally in dendrites, to act as a 40 synthetic substitute for the effect of excitatory and inhibitory presynaptic input.”

“We used a Layer II hippocampal stellate cell model 185 previously published by [32], based on reconstructions from [33].”

“We made no specific assumptions as to the specific type of stimulus 320 representation of the input, such as visual contrast [38], orientation [10] or other 321 stimulus traits; our results hold for the general case in which a driving input at discrete 322 set of location is modulated by neuron-wide distributed drive.”

“Effects of the total dendritic area have 81 been investigated in [29].”

“The TREES toolbox [53] was used for steady-state analysis of injected current in abstract models, and NeuroTools toolbox [54] was used for spiketrain analysis.”

“354 Tracing studies have hinted that within pyramidal cells in sensory areas, there is 355 synaptic targetting with feedforward presynaptic input from the thalamus tends to 356 synapse onto basal dendrites, while input from higher cortical areas instead connects 357 within apical dendrites [34, 41].”

“240 Mechanistically, this is relevant for gain modulation as synaptic input to a neuron is not 241 likely to be uniformly distributed throughout the entire dendritic tree, but may instead 242 be organized by presynaptic origin [21,34].”

“A subsequent 17 theoretical study posits that both mechanisms may be necessary [16], which is supported 18 by experimental evidence from intracellular in vivo recordings [17], indicating that these 19 processes are not mutually exclusive and may instead operate in different regimes.”

“We envisage that computational 379 optogenetic modeling is likely to assist in bridging the gap between computational and 380 experimental studies in areas ranging from neuroscience [42, 43] to cardiac 381”

“Our model of a co-activated opsin utilizes our previously published 6-state models of 443 channelrhodopsin-2 (ChR2) [43,50] and halorhodopsin (NpHR) [51].”

“383 Optogenetic illumination protocols in current use can generally be classified as “hard 384 control”, in which the output of a cell is written directly by using high levels of 385 illumination to induce either spiking or hyperpolarization [45,46].”

“There have been several proposed mechanisms for how a neuron alters 14 the relationship between its input and output, including the use of shunting inhibition to 15 shift the input-output curve [12, 13], and varying the rate of background synaptic noise, 16 decreasing the ability of the neuron to detect target input s…”

“Our model of a co-activated opsin utilizes our previously published 6-state models of 443 channelrhodopsin-2 (ChR2) [43,50] and halorhodopsin (NpHR) [51].”

“Neocortical neurons vary in modulability, with gain modulation having been observed in 6 cortical pyramidal cells from layers 2/3, 5 and 6 [9, 10], whereas input-output 7 relationships in some other cell types, such as entorhinal stellate cells, appear to be 8 much less modulable [11].”

“Increased dendritic inhibition and greater dendritic complexity allow for greater dendritic filtering in vPMCEV neurons (Magee and Johnston, 2005; Capaday and van Vreeswijk, 2006; Muller et al., 2012; Ferrante et al., 2013; Pouille et al., 2013; Jarvis et al., 2018), providing a mechanism to maintain the E:I balance o…”

“In detailed models of pyramidal neuron, the effects of dendritic bifurcation on signal integration were predicted to affect the ability of synaptic input to generate and propagate action potentials [23] and neuronal gain modulation [24].”

“This idea is supported by the unique morphological and physiological properties of pyramidal neurons, as activity in apical dendrites in vivo is generally not sufficient to drive somatic output responses alone ( Stuart and Spruston, 1998 ; Larkum et al., 1999 ; Larkum, 2013 ; Jarvis et al., 2018 ).”

“When it comes to the nervous system, mathematical and computational modelling enables data integration from observations and experiments into a theoretical framework, facilitating the exploitation of the functional role of nervous structures, and neuronal circuits [6] [7] [8] [9].”

“…by a non linear response to its voltage variation, given by : where : Gain control plays an important rule in regulating neurons activity, as it adjusts the relationship between dramatically changing inputs and the limited range of amplitudes in the neuron’s response of neurons [65][66, 67].”

“Dendritic input can change the gain of the neural transfer function on fast timescales (Larkum et al., 2004; Jarvis et al., 2018).”

“It was shown in silico that neuronal gain modulation can be influenced by dendritic morphology (87), and that neuronal firing properties can be influenced by dendrite geometry (88).”