The abilities of neuronal populations to encode rapidly varying stimuli and respond quickly to abrupt input changes are crucial for basic neuronal computations, such as coincidence detection, grouping by synchrony, and spike-timing-dependent plasticity, as well as for the processing speed of neuronal networks. Theoretical analyses have linked these abilities to the fast-onset dynamics of action potentials (APs). Using a combination of whole-cell recordings from rat neocortical neurons and computer simulations, we provide the first experimental evidence for this conjecture and prove its validity for the case of distal AP initiation in the axon initial segment (AIS), typical for cortical neurons. Neocortical neurons with fast-onset APs in the soma can phase-lock their population firing to signal frequencies up to ~300 – 400 Hz and respond within 1–2 ms to subtle changes of input current. The ability to encode high frequencies and response speed were dramatically reduced when AP onset was slowed by experimental manipulations or was intrinsically slow due to immature AP generation mechanisms. Multicompartment conductance-based models reproducing the initiation of spikes in the AIS could encode high frequencies only if AP onset was fast at the initiation site (e.g., attributable to cooperative gating of a fraction of sodium channels) but not when fast onset of somatic AP was produced solely by backpropagation. We conclude that fast-onset dynamics is a genuine property of cortical AP generators. It enables fast computations in cortical circuits that are rich in recurrent connections both within each region and across the hierarchy of areas.
The processing speed of the brain depends on the ability of neurons to rapidly relay input changes. Prior theoretical and experimental studies of the time scale of population firing rate responses arrived at controversial conclusions, some advocating an ultra-fast response scale while others arguing for an inherent disadvantage of mean encoded signals for rapid detection of the stimulus onset. Here we assessed the time scale of population firing rate responses of neocortical neurons in experiments performed in the time domain and the frequency domain in vitro and in vivo. We show that populations of neocortical neurons can alter their firing rate within 1 millisecond in response to somatically delivered weak current signals presented on a fluctuating background. Signals with amplitudes of miniature postsynaptic currents can be robustly and rapidly detected in the population firing. We further show that population firing rate of neocortical neurons in vitro and in vivo can reliably encode weak signals varying at frequencies up to ~200–300 Hz, or ~50 times faster than the firing rate of individual neurons. These results provide coherent evidence for the ultra-fast, millisecond time-scale of cortical population responses. Notably, fast responses to weak stimuli are limited to the mean encoding. Rapid detection of current variance changes requires extraordinarily large signal amplitudes. Our study presents conclusive evidence showing that cortical neurons are capable of rapidly relaying subtle mean current signals. This provides a vital mechanism for the propagation of rate-coded information within and across brain areas.
We study how threshold models and neocortical neurons transfer temporal and interneuronal input correlations to correlations of spikes. In both, we find that the low common input regime is governed by firing rate dependent spike correlations which are sensitive to the detailed structure of input correlation functions. In the high common input regime, the spike correlations are largely insensitive to the firing rate and exhibit a universal peak shape. We further show that pairs with different firing rates driven by common inputs in general exhibit asymmetric spike correlations.
Genetically encoded calcium indicators (GECIs) are mainly represented by two- or one-fluorophore-based sensors. One type of two-fluorophore-based sensor, carrying Opsanus troponin C (TnC) as the Ca2+-binding moiety, has two binding sites for calcium ions, providing a linear response to calcium ions. One-fluorophore-based sensors have four Ca2+-binding sites but are better suited for in vivo experiments. Herein, we describe a novel design for a one-fluorophore-based GECI with two Ca2+-binding sites. The engineered sensor, called NTnC, uses TnC as the Ca2+-binding moiety, inserted in the mNeonGreen fluorescent protein. Monomeric NTnC has higher brightness and pH-stability in vitro compared with the standard GECI GCaMP6s. In addition, NTnC shows an inverted fluorescence response to Ca2+. Using NTnC, we have visualized Ca2+ dynamics during spontaneous activity of neuronal cultures as confirmed by control NTnC and its mutant, in which the affinity to Ca2+ is eliminated. Using whole-cell patch clamp, we have demonstrated that NTnC dynamics in neurons are similar to those of GCaMP6s and allow robust detection of single action potentials. Finally, we have used NTnC to visualize Ca2+ neuronal activity in vivo in the V1 cortical area in awake and freely moving mice using two-photon microscopy or an nVista miniaturized microscope.
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