Miha Pelko PhD

Miha Pelko


Research Interests

My interest and research are focussed on understanding the computational aspects of the single neuron in a realistic in-vivo environment. This includes the comparison between the reductionistic models and more biologically plausible simulations as well as the comparison between the behavior of the neuron in a silent environment as opposed to the behavior in the more natural regime where a neuron is being exposed to the synaptic inputs.

Publications:
2015
  Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output
Schiemann, J, Puggioni, P, Pelko, M, Domanski, A, Van Rossum, M & Duguid, I 2015, 'Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output' Cell Reports, vol 11, no. 8, pp. 1319–1330. DOI: 10.1016/j.celrep.2015.04.042
Neuronal activity in primary motor cortex (M1) correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B) pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed) firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1) a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons), and (2) a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons) that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior.
General Information
Organisations: Edinburgh Neuroscience.
Authors: Schiemann, Julia, Puggioni, Paolo, Pelko, Miha, Domanski, Aleksander, Van Rossum, Mark & Duguid, Ian.
Pages: 1319–1330
Publication Date: 26 May 2015
Publication Information
Category: Article
Journal: Cell Reports
Volume: 11
Issue number: 8
ISSN: 2211-1247
Original Language: English
DOIs: 10.1016/j.celrep.2015.04.042
  Stability of Neuronal Networks with Homeostatic Regulation
Van Rossum, M & Pelko, M 2015, 'Stability of Neuronal Networks with Homeostatic Regulation' PLoS Computational Biology. DOI: 10.1371/journal.pcbi.1004357
Neurons are equipped with homeostatic mechanisms that counteract long-term perturbations of their average activity and thereby keep neurons in a healthy and information-rich operating regime. While homeostasis is believed to be crucial for neural function, a systematic analysis of homeostatic control has largely been lacking. The analysis presented here analyses the necessary conditions for stable homeostatic control. We consider networks of neurons with homeostasis and show that homeostatic control that is stable for single neurons, can destabilize activity in otherwise stable recurrent networks leading to strong non-abating oscillations in the activity. This instability can be prevented by slowing down the homeostatic control. The stronger the network recurrence, the slower the homeostasis has to be. Next, we consider how non-linearities in the neural activation function affect these constraints. Finally, we consider the case that homeostatic feedback is mediated via a cascade of multiple intermediate stages. Counter-intuitively, the addition of extra stages in the homeostatic control loop further destabilizes activity in single neurons and networks. Our theoretical framework for homeostasis thus reveals previously unconsidered constraints on homeostasis in biological networks, and identifies conditions that require the slow time-constants of homeostatic regulation observed experimentally.
General Information
Organisations: Edinburgh Neuroscience.
Authors: Van Rossum, Mark & Pelko, Miha.
Number of pages: 20
Publication Date: 2015
Publication Information
Category: Article
Journal: PLoS Computational Biology
ISSN: 1553-734X
Original Language: English
DOIs: 10.1371/journal.pcbi.1004357
2013
  Behavioral state differentially regulates input sensitivity and firing rates of motor cortex pyramidal neurons
Puggioni, P, Pelko, M, Van Rossum, M & Duguid, I 2013, 'Behavioral state differentially regulates input sensitivity and firing rates of motor cortex pyramidal neurons' BMC Neuroscience, vol 14. DOI: 10.1186/1471-2202-14-S1-P114
The primary motor cortex (M1) plays a prominent role in the initiation and control of voluntary movements [1], but the cellular mechanisms regulating motor output are not well understood. Due to its direct link with behavior, M1 is an ideal platform to study how brain state and behavior are related to single neuron dynamics. Here we combined in vivo patch-clamp recordings and computational modeling to characterize the effects of behavioral state on the membrane potential dynamics and integrative properties of layer 5B pyramidal cells in the awake motor cortex. Furthermore, we injected a range of somatic EPSC-like current pulses during quiet wakefulness and movement to
investigate how behavioral state affects input-output transformations
in layer 5B excitatory neurons.
We found that during quiet wakefulness L5B cells (n = 24) display moderate firing rates (5.6+-3.5 Hz) and depolarized membrane potential (-52.9+-4.4 mV). In superficial and deep cortical layers of M1, we show that the membrane potential during quiet wakefulness is characterized by slow fluctuations in the delta-band range (2-4 Hz), resulting in a large Vm standard deviation (3.5+-1.0 mV) that was similar in magnitude to that observed in L2/3 of
the barrel cortex of awake mice [2].
By modeling the neuron as a single compartment leaky integrate and fire unit, we estimated that the sum of the average excitatory and inhibitory synaptic conductances were similar in magnitude to the leak conductance (<Ge> = 2.2 nS, <Gi> 3.0 nS, Gl = 5.5 nS) and consistent with values measured in primary visual cortex of awake mice [3].
We classified L5B cells (the main output neurons in M1) into two functional different sub-populations, which either suppressed (3.4+-3.5 Hz, L5Bsupp, n = 10) or enhanced (12.7 +- 5.6 Hz, L5Benh, n = 14) their firing rates during movement. During movement, we observed a global suppression of slow Vm fluctuations resulting in a decrease of the Vm standard deviation in L5Bsupp cells (2.4 +-0.3 mV, p = 0.002). By injecting small somatic EPSC waveforms, we demonstrated that the decrease in Vm variance reduced the input sensitivity of L5Bsupp cells during movement. In contrast, L5Benh cells displayed a net depolarization (to -49.1+-4.2 mV, n = 14, p = 0.0006) due to a moderate increase in average excitatory conductance (?Ge = +0.7 nS) and enhanced Vm fluctuations in the high frequency band (12-50 Hz, Figure 1B). Based on integrate-and-fire simulations, we estimate that during movement excitatory inputs to L5Benh cells increased by +30%, with enhanced fine time-scale correlations (pairwise correlation coefficient of the inputs is ~1% larger). These changes increased the input sensitivity of L5Benh neurons. Thus we find that behavioural state differentially regulates the membrane potential dynamics and integrative properties of discrete subpopulations of output neurons in M1.
Our findings suggest that sensorimotor information is preferentially routed through distinct subpopulations of excitatory neurons during motor behavior. During movement motor output from M1 is controlled by the interplay between a global suppression of slow Vm fluctuations and selective increase in the rate and synchrony of excitatory synaptic inputs.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Puggioni, Paolo, Pelko, Miha, Van Rossum, Mark & Duguid, Ian.
Publication Date: 2013
Publication Information
Category: Meeting abstract
Journal: BMC Neuroscience
Volume: 14
ISSN: 1471-2202
Original Language: English
DOIs: 10.1186/1471-2202-14-S1-P114
  Integrative properties of motor cortex pyramidal cells during quiet wakefulness and movement
Puggioni, P, Pelko, M, Van Rossum, M & Duguid, I 2013, 'Integrative properties of motor cortex pyramidal cells during quiet wakefulness and movement' Computational and Systems Neuroscience (Cosyne) 2013, Salt Lake City, Utah, United States, 28/02/13 - 5/03/13, pp. 190.
The primary motor cortex (M1) plays a prominent role in the initiation and control of voluntary movements. Due to its direct link with behaviour, M1 is an ideal platform to study how brain state and behaviour are related to single neuron dynamics. We perform patch-clamp recordings and somatic current injections in the M1 of awake mice to characterise the intracellular activity and integrative properties of excitatory neurons in supercial (L2/3) and deep (L5B) layers during quiet wakefulness and movement. We find that during quiet wakefulness, L2/3 neurons display sparse spiking activity (0.5+0.7 Hz) while L5B cells display sustained firing (5.6+3.5 Hz) and that the membrane potential (Vm) in both cortical layers is characterized by slow fluctuations in the delta-band range (2-4 Hz). We identified two subpopulations of pyramidal cells in L5B -the main output layer of M1- that either suppressed (L5Bsupp) or enhanced (L5Benh) their firing rates during movement. In L5Bsupp neurons, movement decreased slow Vm oscillations and variance with no change in mean Vm, resulting in divisive gain modulation and reduced spike rates. In L5Benh neurons, movement also reduced slow Vm oscillations but this effect was counterbalanced by a net depolarization and increased Vm fluctuations in the high frequency band (12-50 Hz), resulting in increased firing rates. Based on integrate-and-fire simulations, we estimate that during movement L5Benh neurons preferentially receive an increase in excitatory inputs (%) with more substantial correlations on a fine time-scale. Together, these changes have a linear multiplicative effect on the input-output gain of L5Benh neurons. Our data demonstrate a remarkable diversity among cortical layers, a strong modulation of integrative properties depending on brain state and suggest that the cortex exploits behavior-dependent modes of operation.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Puggioni, Paolo, Pelko, Miha, Van Rossum, Mark & Duguid, Ian.
Publication Date: 2013
Publication Information
Category: Poster
Original Language: English
2012
  Determining synaptic input properties from intra-cellular recordings in vivo
Pelko, M, Puggioni, P, Van Rossum, M & Bouscein, C 2012, 'Determining synaptic input properties from intra-cellular recordings in vivo'.
A cortical neuron in vivo is bombarded with excitatory and inhibitory inputs that eventually underlie the neuron's activity. The transformation between input and output, which is determined by the synaptic integration and the action potential generation, is core to neural information processing and neural coding. However, despite its importance the precise transformation between input and output is unclear.
Although it is currently impossible to exactly measure all the presynaptic spike trains to a specific neuron, much can be learned from recordings of the post-synaptic membrane potential. In this study we outline a procedure to estimate the presynaptic activity based on the statistics of the membrane voltage obtained in in-vivo patch- clamping experiments. In particular, we include analysis of the power-spectral density and the frequency of events of a certain size.
We apply the above procedure to measurements of the membrane voltage fluctuations in motor cortex of awake mice during the resting state and a spontaneous movement state. The results allow us to suggest an explanation for the observed changes between the two states.
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Pelko, Miha, Puggioni, Paolo, Van Rossum, Mark & Bouscein, Clemens.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English
  Layer specific sub- and suprathreshold coding of voluntary movements in the motor cortex of awake mice
Puggioni, P, Pelko, M, Van Rossum, M & Duguid, I 2012, 'Layer specific sub- and suprathreshold coding of voluntary movements in the motor cortex of awake mice' Society for Neuroscience Annual Meeting 2012, New Orleans, 13/10/12 - 17/10/12, .
Intracellular recordings of neurons in vivo are becoming routine, yielding rich insights in neural dynamics and the integration of information by neurons under realistic situations. In particular, these methods have been used to estimate the mean excitatory and mean inhibitory conductances experienced by the soma.
We first present a novel method to estimate the effective somatic excitatory and inhibitory conductance as well as their rate and event size from the intracellular in vivo recordings. We apply this technique to the intracellular recordings from the primary motor cortex of awake behaving mice.
Next, we study how dendritic filtering affects these estimates. While the effects of the inputs on the conductance change are mostly local, the effects on the membrane voltage extend further, resulting in the misestimation of the compound excitatory and inhibitory conductances. Using analytical treatment of a simplified model and simulations in a detailed model, we show how much both the mean as well as the variation of the dendritic synaptic conductances are underestimated
by the methods based on conductance measurements at the soma. We discuss the influence of the synaptic distance from the soma on the underestimation for both excitatory as well as inhibitory inputs for different realistic neuronal morphologies.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Puggioni, Paolo, Pelko, Miha, Van Rossum, Mark & Duguid, Ian.
Keywords: (in vivo, intracellular recordings, simulations. )
Publication Date: Oct 2012
Publication Information
Category: Poster
Original Language: English
  Membrane Voltage Dynamics in Active vs. Passive Mice: The Role of Input Correlations
Pelko, M & Van Rossum, M 2012, 'Membrane Voltage Dynamics in Active vs. Passive Mice: The Role of Input Correlations' 8th Fens Forum of Neuroscience, Barcelona, Spain, 14/07/12 - 18/07/12, .
Recent reports of intracellular in-vivo recordings in barrel cortex [1] and primary motor cortex [2] of awake mice reveal two regimes of sub-cellular membrane potential activity and suggest the existence of two distinct network states. In active states, when the mouse is whisking or running, the variance of the sub-threshold membrane voltage decreases and the mean of the membrane voltage increases compared to the passive state when the mouse is not whisking and not moving. Yet the firing rates in both states are comparable.
In this modelling study of a pyramidal cell we explore possible mechanisms behind the two regimes of sub-threshold membrane potential fluctuations. While constraining the total input - the number of presynaptic spikes - we show that the change in the correlation structure of inputs is sufficient to explain the shifts in the mean and the variance of the sub-threshold membrane potential in the two regimes.

References:
[1] James F. A. Poulet and Carl C. H. Petersen, “Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice,” Nature 454, no. 7206 (2008): 881-885.
[2] Puggioni et al., “Layer Specific Sub- and Suprathreshold Coding of Voluntary Movements in the Motor Cortex of Awake Mice”, FENS Forum Abstr.
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Pelko, Miha & Van Rossum, Mark.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English
2011
  The effects of input integration structure on the spiking responses in the Hodgin-Huxley models
Pelko, M & Van Rossum, M 2011, 'The effects of input integration structure on the spiking responses in the Hodgin-Huxley models' Mathematical Neuroscience 2011, Edinburgh, United Kingdom, 11/04/11 - 13/04/11, .
For the neurons in the fluctuation regime correlations in the inputs can significantly alter the neuronal output. Here we investigate how the output is affected by input with different correlation profiles beyond the pairwise correlations.
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Pelko, Miha & Van Rossum, Mark.
Publication Date: 2011
Publication Information
Category: Poster
Original Language: English

Projects:
Synaptic integration in neurons under in vivo-like conditions (PhD)