Intrinsic excitability mechanisms of neuronal ensemble formation

Abstract

Neuronal ensembles are coactive groups of cortical neurons, found in spontaneous and evoked activity, that can mediate perception and behavior. To understand the mechanisms that lead to the formation of ensembles, we co-activated layer 2/3 pyramidal neurons in brain slices from mouse visual cortex, in animals of both sexes, replicating in vitro an optogenetic protocol to generate ensembles in vivo. Using whole-cell and perforated patch-clamp pair recordings we find that, after optogenetic or electrical stimulation, coactivated neurons increase their correlated activity, a hallmark of ensemble formation. Coactivated neurons showed small biphasic changes in presynaptic plasticity, with an initial depression followed by a potentiation after a recovery period. Optogenetic and electrical stimulation also induced significant increases in frequency and amplitude of spontaneous EPSPs, even after single-cell stimulation. In addition, we observed unexpected strong and persistent increases in neuronal excitability after stimulation, with increases in membrane resistance and reductions in spike threshold. A pharmacological agent that blocks changes in membrane resistance can revert this effect. These significant increases in excitability may partly generate the observed biphasic synaptic plasticity. We propose that cell-intrinsic changes in excitability are involved in the formation of neuronal ensembles. We propose an 'iceberg' model, by which increased neuronal excitability makes subthreshold connections suprathreshold, enhancing the effect of already existing synapses, and generating a new neuronal ensemble.

A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking

“…We also found that the stability of dCA1 coactivity patterns is impaired by the inhibition of LC cells projecting to dCA1 [98]. Importantly, this finding was confirmed by both general pairwise correlations and by methods of cell assembly detection that identify groups of neurons that fire together.…”

“…Importantly, this finding was confirmed by both general pairwise correlations and by methods of cell assembly detection that identify groups of neurons that fire together. Recent findings suggested that the short-term (minutes to hours) stabilization of neuronal assemblies is mediated by changes in intrinsic excitability [98]. Moreover, dopaminergic modulation of dCA1 leads to increases in neuronal coactivity, post learning reactivation of these coactivity patterns, and improved behavioral performance [99].…”

Formation and computational implications of assemblies in neural circuits

“…Despite recent efforts to show experimentally that an ensemble also consists of strong, connected neurons (e.g. Alejandre‐García et al., 2022), a clear link is still missing.…”

“…While this increased correlated firing and spontaneous reactivations of the stimulated subgroup of neurons over days, the underlying mechanism has remained unclear. Long‐term synaptic plasticity that leads to stronger recurrent inputs is one possibility (Zhang et al., 2020), but a change in the neuron's intrinsic excitability is also possible (Alejandre‐García et al., 2022; Debanne et al., 2019; Zhang & Linden, 2003). Increased intrinsic excitability also plays an important role in memory formation.…”

Amplified cortical neural responses as animals learn to use novel activity patterns

“…These outside sources might be changes in top-down, higher-order thalamic (e.g., from the lateral posterior nucleus, LP / pulvinar) or neuromodulatory input that change the gain of V1 neurons. In addition, individual cells might change their intrinsic excitability 76 . However, were top-down input changes, intrinsic excitability, or neuromodulatory effects the dominant players, we might expect effects on visual responses as well.…”