The role of gain neuromodulation in layer-5 pyramidal neurons
Alejandro Rodriguez-Garcia*1, Christopher J. Whyte2, Brandon R. Munn2, Jie Mei3,4,5, James M. Shine2, Srikanth Ramaswamy1,6
1Neural Circuits Laboratory, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
2Brain and Mind Center, The University of Sydney, Sydney, Australia, Center for Complex Systems, The University of Sydney, Sydney, Australia
3IT:U Interdisciplinary Transformation University Austria, Linz, Austria
4International Research Center for Neurointelligence, The University of Tokyo, Tokyo, Japan
5Department of Anatomy, University of Quebec in Trois-Rivieres, Trois-Rivieres, QC, Canada
6Theoretical Sciences Visiting Program (TSVP), Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
*Email: a.rodriguez-garcia2@newcastle.ac.uk
Introduction
Layer-5 pyramidal neurons exhibit BAC firing, where distal dendritic inputs coincide with somatic backpropagating action potentials (BAPs) to trigger Ca²⁺ spikes, converting isolated spikes into bursts and increasing gain[1]. This mechanism is essential for cognitive functions like attention and perceptual shifts[2, 3]. The ascending arousal system flexibly reconfigures neuronal activity during perceptual shifts while maintaining network stability[4, 5]. Here, we explore the role of gain neuromodulation in learning using a biophysically plausible network of layer-5 pyramidal neurons with dendritic-targeting somatostatin (SOM) and somatic-targeting parvalbumin (PV) interneurons.
Methods
We developed a two-compartment Izhikevich neuron model with separate somatic and apical dendritic compartments. The apical dendritic compartment is a 2D nonlinear system governing Ca²⁺ spike generation[3, 6]. The somatic and dendritic compartments are coupled so that somatic sodium spikes trigger BAPs, while dendritic plateau potentials switch somatic activity from regular spiking to bursting. This shift is achieved by increasing the post-spike reset voltage and reducing the spike adaptation in the somatic compartment. BAP events occur stochastically[7], controlled by a soma‐apical coupling parameter. Neuromodulatory signals modulate apical drive and coupling to adjust somatic gain[8–10]. The model is embedded in a toroidal network geometry that incorporates SOM and PV interneurons. Connectivity follows a Gaussian profile[3, 4], and synapses exhibit plasticity via STDP[11].
Results
Simulations demonstrate that both increased dendritic drive and enhanced somatic-apical coupling effectively elevate the gain of pyramidal neurons, likely due to hysteresis in the apical compartment that generates a transient stable state above the calcium threshold (Fig.1A,B). In contrast, dendritic-targeted inhibition reduces gain, while somatic-targeting inhibition significantly raises the adjacent neurons firing threshold (Fig.1C). Capturing these dynamics at the network level leads to a reconfiguration of activity, as burst-like behavior increases spike frequency and accelerates STDP weight updates, rapidly resetting the network to adapt to changing input streams.
Discussion
Our findings highlight the critical role of neuromodulatory control over pyramidal gain through a biologically-informed framework[12], providing a mechanistic explanation for transitions between flexible and stable network states by evaluating its effects to STDP plasticity, in line with previous studies[2–4]. Dendritic-targeted inhibition reduces gain, while somatic-targeted inhibition raises the firing threshold, following experimental observations[13], providing an inhibitory gating control[14]. Future work will leverage neuromodulatory signals to induce flexible, stable neural processing for adaptive learning in biological and neuromorphic systems.
Figure 1. Study of layer-5 neurons with PV and SOM inhibition. (A) Schematic of the model in isolation. (B) Hysteresis in the apical compartment induced by increasing apical drive. (C) Gain enhancement resulting from soma-apical coupling. (D) Gain reduction achieved through dendritic-targeted inhibition. (E) Elevation of the firing threshold via somatic-targeted inhibition.
Acknowledgements
This work was supported by the Lister Institute Prize Fellowship to S.R.; Newcastle University Academic Track (NUAcT) Fellowship to S.R.; NUAcT PhD studentship to A.R-G. J.M. acknowledges support from the Japan Society for the Promotion of Science (JSPS) and the Japan Science and Technology Agency (JST). J.M.S. was supported by the National Health and Medical Research Council (GNT1193857).
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