Cellular mechanisms for response heterogeneity among L2/3 pyramidal cells in whisker somatosensory cortex

Whisker deflection evokes sparse, low-probability spiking among L2/3 pyramidal cells in rodent somatosensory cortex (S1), with spiking distributed nonuniformly between more and less responsive cells. The cellular and local circuit factors that determine whisker responsiveness across neurons are unclear. To identify these factors, we used two-photon calcium imaging and loose-seal recording to identify more and less responsive L2/3 neurons in S1 slices in vitro, during feedforward recruitment of the L2/3 network by L4 stimulation. We observed a broad gradient of spike recruitment thresholds within local L2/3 populations, with low- and high-threshold cells intermixed. This recruitment gradient was significantly correlated across different L4 stimulation sites, and between L4-evoked and whisker-evoked responses in vivo, indicating that a substantial component of responsiveness is independent of tuning to specific feedforward inputs. Low- and high-threshold L2/3 pyramidal cells differed in L4-evoked excitatory synaptic conductance and intrinsic excitability, including spike threshold and the likelihood of doublet spike bursts. A gradient of intrinsic excitability was observed across neurons. Cells that spiked most readily to L4 stimulation received the most synaptic excitation but had the lowest intrinsic excitability. Low- and high-threshold cells did not differ in dendritic morphology, passive membrane properties, or L4-evoked inhibitory conductance. Thus multiple gradients of physiological properties exist across L2/3 pyramidal cells, with excitatory synaptic input strength best predicting overall spiking responsiveness during network recruitment.

The state of somatosensory cortex during neuromodulation

During behavioral quiescence, such as slow-wave sleep and anesthesia, the neocortex is in a deactivated state characterized by the presence of slow oscillations. During arousal, slow oscillations are absent and the neocortex is in an activated state that greatly impacts information processing. Neuromodulators acting in neocortex are believed to mediate these state changes, but the mechanisms are poorly understood. We investigated the actions of noradrenergic and cholinergic activation on slow oscillations, cellular excitability, and synaptic inputs in thalamocortical slices of somatosensory cortex. The results show that neuromodulation abolishes slow oscillations, dampens the excitability of principal cells, and rebalances excitatory and inhibitory synaptic inputs in thalamocortical-recipient layers IV–III. Sensory cortex is much more selective about the inputs that can drive it. The source of neuromodulation is critically important in determining this selectivity. Cholinergic activation suppresses the excitatory and inhibitory conductances driven by thalamocortical and intracortical inputs. Noradrenergic activation suppresses the excitatory conductance driven by intracortical inputs but not by thalamocortical inputs and enhances the inhibitory conductance driven by thalamocortical inputs but not by intracortical inputs. Thus noradrenergic activation emphasizes thalamocortical (sensory) inputs relative to intracortical inputs, while cholinergic activation suppresses both.

High-frequency, short-latency disinhibition bursting of midbrain dopaminergic neurons

During reinforcement and sequence learning, dopaminergic neurons fire bursts of action potentials. Dopaminergic neurons in vivo receive strong background excitatory and inhibitory inputs, suggesting that one mechanism by which bursts may be produced is disinhibition. Unfortunately, these inputs are lost during slice preparation and are not precisely controlled during in vivo experiments. In the present study we show that dopaminergic neurons can be shifted into a balanced state in which constant synaptic N-methyl-d-aspartate (NMDA) and GABAA conductances are mimicked either pharmacologically or using dynamic clamp. From this state, a disinhibition burst can be evoked by removing the background inhibitory conductance. We demonstrate three functional characteristics of network-based disinhibition that promote high-frequency, short-latency bursting in dopaminergic neurons. First, we found that increasing the total background NMDA and GABAA synaptic conductances increased the intraburst firing frequency and reduced its latency. Second, we found that the disinhibition burst is sensitive to the proportion of background inhibitory input that is removed. In particular, we found that high-frequency, short-latency bursts were enhanced by increasing the degree of disinhibition. Third, the time course over which inhibition is removed had a large effect on the burst, namely, that synchronous removal of weak inhibitory inputs produces bursts of high intraburst frequency and shorter latency. Our results suggest that fast, more precisely timed bursts can be evoked by complete and synchronous disinhibition of dopaminergic neurons in a high-conductance state.

Partial Disinhibition Is Required for Transition of Stimulus-Induced Sharp Wave–Ripple Complexes Into Recurrent Epileptiform Discharges in Rat Hippocampal Slices

Sharp wave–ripple complexes (SPW-Rs) in the intact rodent hippocampus are characterized by slow field potential transients superimposed by close to 200-Hz ripple oscillations. Similar events have been recorded in hippocampal slices where SPW-Rs occur spontaneously or can be induced by repeated application of high-frequency stimulation, a standard protocol for induction of long-lasting long-term potentiation. Such stimulation is reminiscent of protocols used to induce kindling epilepsy and ripple oscillations may be predictive of the epileptogenic zone in temporal lobe epilepsy. In the present study, we investigated the relation between recurrent epileptiform discharges (REDs) and SPW-Rs by studying effects of partial removal of inhibition. In particular, we compared the effects of nicotine, low-dose bicuculline methiodide (BMI), and elevated extracellular potassium concentration ([K+]o) on induced SPW-Rs. We show that nicotine dose-dependently transformed SPW-Rs into REDs. This transition was associated with reduced inhibitory conductance in CA3 pyramidal cells. Similar results were obtained from slices where the GABAergic conductance was reduced by application of low concentrations of BMI (1–2 μM). In contrast, sharp waves were diminished by phenobarbital. Elevating [K+]o from 3 to 8.5 mM did not transform SPW-Rs into REDs but significantly increased their incidence and amplitude. Under these conditions, the equilibrium potential for inhibition was shifted in depolarizing direction, whereas inhibitory conductance was significantly increased. Interestingly, the propensity of elevated [K+]o to induce seizure-like events was reduced in slices where SPW-Rs had been induced. In conclusion, recruitment of inhibitory cells during SPW-Rs may serve as a mechanism by which hyperexcitation and eventually seizure generation might be prevented.