A Fast Markovian Method For Modeling Channel Noise In Neurons

Channel noise results from rapid transitions of protein channels from closed to open state and is generally considered as the most dominant source of electrical noise causing membrane-potential fluctuations even in the absence of synaptic inputs. The simulation of a realistic channel noise remains a source of possible error. Although the Markovian method is considered as the golden standard for appropriate description of channel noise, its computation time increasing exponentially with numbers of channels, it is poorly suitable to simulate realistic features. We describe here a novel algorithm for simulating ion channel noise based on Markov chains (MC). Although this new algorithm refers to a Monte-Carlo process, it only needs few random numbers whatever the number of channels involved. Our fast MC (FMC) model does not exhibit the drawbacks due to approximations based on stochastic differential equations. In fact, we show here, that these drawbacks can be highlighted even for a high number of channels.

Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons

Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson’s disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.

Voltage-sensitive dye imaging reveals inhibitory modulation of ongoing cortical activity

Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. In particular, it is unclear how VSDI signals relate to population firing rates. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5. We proceed by exploring experimentally inaccessible circuit properties to show that during periods of spontaneous activity, membrane potential fluctuations are anticorrelated with population firing rates. Furthermore, we manipulate network connections to show that this effect depends on recurrent connectivity and is modulated by external input. We conclude that VSDI primarily reflects inhibitory responses to ongoing excitatory dynamics.

Direct Pathway Neurons in Mouse Dorsolateral Striatum In Vivo Receive Stronger Synaptic Input than Indirect Pathway Neurons

Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1 or D2 type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modelling of the striatal network has predicted that under healthy conditions dMSNs should receive more excitatory input than iMSNs. To test this prediction, we analyzed in vivo whole-cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized towards the spike threshold significantly faster than iMSNs did. Together, these finding corroborate the theoretical prediction that direct-pathway MSNs receive stronger input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question how a lack of dopamine may lead to behavior deficits associated with Parkinson’s disease.Significance statementThe direct and indirect pathways of the basal ganglia originate from the D1 and D2 type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs), respectively. To understand the role of the striatum in brain function and dysfunction it is important to characterize the differences in synaptic inputs to the two MSN types. Theoretical results predicted that dMSNs should receive stronger excitatory input than iMSNs. Here, we studied membrane potential fluctuation statistics of MSNs recorded in vivo in anaesthetized mice and found that dMSNs, indeed, received stronger synaptic input than iMSNs. We corroborated this finding by spike-triggered membrane potential analysis, showing that dMSNs spiking required more synaptic input than iMSNs spiking did, as had been predicted by computational models.

Single-cell membrane potential fluctuations evince network scale-freeness and quasicriticality

What information single neurons receive about general neural circuit activity is a fundamental question for neuroscience. Somatic membrane potential fluctuations are driven by the convergence of synaptic inputs from a diverse cross-section of upstream neurons. Furthermore, neural activity is often scale-free implying that some measurements should be the same, whether taken at large or small scales. Together, convergence and scale-freeness support the hypothesis that single membrane potential recordings carry useful information about high-dimensional cortical activity. Conveniently, the theory of "critical branching networks" (a purported explanation for scale-freeness) provides testable predictions about scale-free measurements which are readily applied to membrane potential fluctuations. To investigate, we obtained whole-cell current clamp recordings of pyramidal neurons in visual cortex of turtles with unknown genders. We isolated fluctuations in membrane potential below the firing threshold and analyzed them by adapting the definition of "neuronal avalanches" (spurts of population spiking). The membrane potential fluctuations we analyzed were scale-free and consistent with critical branching. These findings recapitulated results from large-scale cortical population data obtained separately in complementary experiments using microelectrode arrays (previously published (Shew et al., 2015)). Simultaneously recorded single-unit local field potential did not provide a good match; demonstrating the specific utility of membrane potential. Modeling shows that estimation of dynamical network properties from neuronal inputs is most accurate when networks are structured as critical branching networks. In conclusion, these findings extend evidence for critical branching while also establishing subthreshold pyramidal neuron membrane potential fluctuations as an informative gauge of high-dimensional cortical population activity.

Proximodistal organization of the CA2 hippocampal area

The proximodistal axis is considered a major organizational principle of the hippocampus. Interfacing between the hippocampus and other brain systems, the CA2 region apparently breaks this rule. Apart from its specific role in social memory, CA2 has been involved in temporal and contextual memory but mechanisms remain elusive. Here, we used intracellular and extracellular recordings followed by neurochemical identification of single-cells to evaluate CA2 and surrounding areas in the rat. We found marked proximodistal trends of synaptic activity, as well as in subthreshold membrane potentials and phase-locked firing coupled to theta and gamma oscillations. Opposite proximodistal correlations between membrane potential fluctuations and theta sinks and sources at different layers revealed influences from up to three different generators. CA2 memory engrams established after a social memory task reflected these trends. We suggest that the structure and function of CA2 is segregated along the proximodistal hippocampal axis.

Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output.