Neuronal complex bursts and network information transfer in the hippocampus are robust to biophysical heterogeneities

Abstract

Biological entities must adopt mechanisms to override the impact of external perturbations to achieve stability and robustness. A crucial feature of biological systems is that they exhibit several forms of heterogeneities spanning all scales of functional analysis. A central question on biological robustness is therefore its relationship to heterogeneities, specifically addressing details pertaining to whether biological heterogeneities promote or impede robustness. In this thesis, we chose the mammalian CA3 sub-region of the hippocampus to be the system of interest towards understanding the impact of the biophysical heterogeneities on the functional robustness across the cellular and network scales.

Heterogeneities at the cellular scale are associated with the intrinsic properties of the CA3 pyramidal neurons as well as with synaptic inputs. The overall goal here was to assess the robust emergence of neuronal intrinsic properties (input resistance, back-propagating action potential amplitude, bursting and spiking profiles) along with complex spike bursting (CSB) in the CA3 pyramidal neurons with respect to heterogeneities in their parametric and measurement spaces. We generated a heterogeneous population of 12,000 random morphologically and biophysically realistic CA3 pyramidal neurons spanning a broad spectrum of parameters. We found two functional sub-classes of intrinsic bursting and regular spiking neurons, with significant differences in the expression profiles of N-type calcium and calcium-activated potassium (SK) channels. By triggering CSBs in all valid models using a variety of protocols, we observed substantial heterogeneities in the CSB propensities across models and protocols. Employing the virtual knockout approach for 7 different ion channels and N-methyl-D-aspartate receptors individually, we noted that synergistic interactions between several intrinsic and synaptic components regulated the robust emergence of CSB in these neurons. Together, we demonstrate the expression of ion-channel degeneracy in the robust emergence of physiological properties of CA3 pyramidal neurons including CSB, despite pronounced heterogeneities in their intrinsic and synaptic components.

Heterogeneities at the network scale are associated with intrinsic and synaptic components, with synaptic heterogeneities spanning local connections as well as afferent inputs from other brain regions. In this part of the thesis, we assessed the impact of neural-circuit heterogeneities, balance between excitatory and inhibitory synaptic strengths, and trial-to-trial variability on the spatial tuning profiles and spatial information transfer in the CA3 recurrent network. We employed homogeneous and heterogenous networks and stimulated them with spatially modulated inputs and employed the stimulus-specific information (SSI) metric to quantify the spatial information transfer by the place cells in these networks. We observed notable heterogeneities in spatial information transfer across both homogeneous and heterogeneous networks, with information transfer also dependent on synaptic inhibition strengths and trial-to-trial variabilities. Strikingly, spatial information transfer was robust to relatively higher noise levels in the heterogeneous networks compared to their homogeneous counterparts, thereby highlighting a crucial role for neural heterogeneities in enhancing the robustness of spatial information transfer in a recurrent place-cell network. We also found that a precise balance between recurrent and afferent connectivity was essential to maintain optimal spatial information transfer in neurons of such networks. Our analyses postulate a critical role for intrinsic heterogeneities in enhancing the robustness of spatial information transfer in a recurrent network of spatially tuned neurons.

Together, these analyzes point to a beneficial role for neural heterogeneities in the robustness of single-neuron and network physiology in the CA3 sub-region of the hippocampus.