Mitochondria decode firing frequency and coincidences of postsynaptic APs and EPSPs

Mitochondrial metabolism is critical for brain function. However, the mechanisms linking mitochondrial energy production to neuronal activity are elusive. Using whole-cell electrical recordings from Layer 5 pyramidal neurons in cortical slices and fluorescence imaging of cytosolic, mitochondrial Ca2+ indicators and endogenous NAD(P)H, we revealed ultra-fast, spike-evoked mitochondrial Ca2+ transients temporally similar to cytosolic Ca2+ elevations. We demonstrate that, whereas single or few spikes elicit the mitochondrial Ca2+ transients throughout the cell, their amplitude is differentially regulated in distinct neuronal compartments. Thus, these signals were prominent in the soma and apical dendrites and ~3 times smaller in basal dendrites and axons. The spike firing frequency had a subtle effect on the amplitude of the cytosolic Ca2+ elevations but dramatically affected mitochondrial Ca2+ transients and NAD(P)H oxidation and recovery rates. Moreover, while subthreshold EPSPs alone caused no detectable Ca2+ elevation in dendritic mitochondria, the Hebbian coincidence of unitary EPSP and postsynaptic spike produced a localized, single mitochondrial Ca2+ elevation. These findings suggest that neuronal mitochondria are uniquely capable of decoding firing frequency and EPSP-to-spike time intervals for tuning the metabolic rate and triggering changes in synaptic efficacy.

Three rules govern thalamocortical connectivity of fast-spike inhibitory interneurons in the visual cortex

Some cortical neurons receive highly selective thalamocortical (TC) input, but others do not. Here, we examine connectivity of single thalamic neurons (lateral geniculate nucleus, LGN) onto putative fast-spike inhibitory interneurons in layer 4 of rabbit visual cortex. We show that three ‘rules’ regulate this connectivity. These rules concern: (1) the precision of retinotopic alignment, (2) the amplitude of the postsynaptic local field potential elicited near the interneuron by spikes of the LGN neuron, and (3) the interneuron’s response latency to strong, synchronous LGN input. We found that virtually all first-order fast-spike interneurons receive input from nearly all LGN axons that synapse nearby, regardless of their visual response properties. This was not the case for neighboring regular-spiking neurons. We conclude that profuse and highly promiscuous TC inputs to layer-4 fast-spike inhibitory interneurons generate response properties that are well-suited to mediate a fast, sensitive, and broadly tuned feed-forward inhibition of visual cortical excitatory neurons.

Diversity of γ-ray and radio variability of bright blazars and implications for γ-ray emission location

Violent multi-wavelength variabilities are observed in γ-ray-selected blazars. We present an analysis of long-term light curves for eight bright blazars to explore the co-variation pattern in the γ-ray and radio bands. We extract their γ-ray light curves and spectra with data observed by the Fermi Large Area Telescope (LAT) since 2008. We find diverse co-variation patterns between the γ-ray and radio (at 43 GHz) fluxes in these sources. The γ-ray and radio fluxes of 3C 454.3 and PKS 1633+382 are correlated without any time lag, suggesting that they are from the same radiation region. Similar correlation is also observed in 3C 273 and PKS 1222+216, but the radio flux lags behind the γ-ray flux by approximately ∼160 d and ∼290 d, respectively. This likely suggests that their γ-ray emission regions are located the upstream of their radio cores at 43 GHz. The γ-ray and radio fluxes of the other four blazars are not correlated, implying that the γ-ray and radio emission may be from different regions in their jets. The γ-ray light curves of the eight blazars can be decomposed into some components with long-timescale variability and some fast spike flares. We propose that they may be attributed to the central engine activity and the magnetic reconnection process or turbulence in the local emission region, respectively.

Training and spontaneous reinforcement of neuronal assemblies by spike timing plasticity

The synaptic connectivity of cortex is plastic, with experience shaping the ongoing interactions between neurons. Theoretical studies of spike timing–dependent plasticity (STDP) have focused on either just pairs of neurons or large-scale simulations. A simple analytic account for how fast spike time correlations affect both micro- and macroscopic network structure is lacking. We develop a low-dimensional mean field theory for STDP in recurrent networks and show the emergence of assemblies of strongly reciprocally coupled neurons with shared stimulus preferences. After training this connectivity is actively reinforced by spike train correlations during the spontaneous dynamics. Furthermore, the stimulus coding by cell assemblies is actively maintained by these internally generated spiking correlations, suggesting a new role for noise correlations in neural coding. Assembly formation has been often associated with firing rate-based plasticity schemes; our theory provides an alternative and complementary framework, where fine temporal correlations and STDP form and actively maintain learned structure in cortical networks.

Alterations in functional thalamocortical connectivity following neonatal whisker trimming with adult regrowth

Neonatal whisker trimming followed by adult whisker regrowth leads to higher responsiveness and altered receptive field properties of cortical neurons in corresponding layer 4 barrels. Studies of functional thalamocortical (TC) connectivity in normally reared adult rats have provided insights into how experience-dependent TC synaptic plasticity could impact the establishment of feedforward excitatory and inhibitory receptive fields. The present study employed cross-correlation analyses to investigate lasting effects of neonatal whisker trimming on functional connections between simultaneously recorded thalamic neurons and regular-spike (RS), presumed excitatory, and fast-spike (FS), presumed inhibitory, barrel neurons. We find that, as reported previously, RS and FS cells in whisker-trimmed animals fire more during the earliest phase of their whisker-evoked responses, corresponding to the arrival of TC inputs, despite a lack of change or even a slight decrease in the firing of thalamic cells that contact them. Functional connections from thalamus to cortex are stronger. The probability of finding TC-RS connections was twofold greater in trimmed animals and similar to the frequency of TC-FS connections in control and trimmed animals, the latter being unaffected by whisker trimming. Unlike control cases, trimmed RS units are more likely to receive inputs from TC units (TCUs) and have mismatched angular tuning and even weakly responsive TCUs make strong functional connections on them. Results indicate that developmentally appropriate tactile experience early in life promotes the differential thalamic engagement of excitatory and inhibitory cortical neurons that underlies normal barrel function.

Weaker feedforward inhibition accounts for less pronounced thalamocortical response transformation in mouse vs. rat barrels

Feedforward inhibition is a common motif of thalamocortical circuits. Strong engagement of inhibitory neurons by thalamic inputs enhances response differentials between preferred and nonpreferred stimuli. In rat whisker-barrel cortex, robustly driven inhibitory barrel neurons establish a brief epoch during which synchronous or near-synchronous thalamic firing produces larger responses to preferred stimuli, such as high-velocity deflections of the principal whisker in a preferred direction. Present experiments in mice show that barrel neuron responses to preferred vs. nonpreferred stimuli differ less than in rats. In addition, fast-spike units, thought to be inhibitory barrel neurons, fire less robustly to whisker stimuli in mice than in rats. Analyses of real and simulated data indicate that mouse barrel circuitry integrates thalamic inputs over a broad temporal window, and that, as a consequence, responses of barrel neurons are largely similar to those of thalamic neurons. Results are consistent with weaker feedforward inhibition in mouse barrels. Differences in thalamocortical circuitry between mice and rats may reflect mechanical properties of the whiskers themselves.