Michael London

Sensitivity to perturbations in vivo implies high noise and suggests rate coding in cortex.

It is well known that neural activity exhibits variability, in the sense that identical sensory stimuli produce different responses, but it has been difficult to determine what this variability means. Is it noise, or does it carry important information—about, for example, the internal state of the organism? Here we address this issue from the bottom up, by asking whether small perturbations to activity in cortical networks are amplified. Based on in vivo whole-cell patch-clamp recordings in rat barrel cortex, we find that a perturbation consisting of a single extra spike in one neuron produces approximately 28 additional spikes in its postsynaptic targets. We also show, using simultaneous intra- and extracellular recordings, that a single spike in a neuron produces a detectable increase in firing rate in the local network. Theoretical analysis indicates that this amplification leads to intrinsic, stimulus-independent variations in membrane potential of the order of ±2.2–4.5 mV—variations that are pure noise, and so carry no information at all. Therefore, for the brain to perform reliable computations, it must either use a rate code, or generate very large, fast depolarizing events, such as those proposed by the theory of synfire chains. However, in our in vivo recordings, we found that such events were very rare. Our findings are thus consistent with the idea that cortex is likely to use primarily a rate code.

The site of action potential initiation in cerebellar Purkinje neurons.

Knowledge of the site of action potential initiation is essential for understanding how synaptic input is converted into neuronal output. Previous studies have shown that the lowest-threshold site for initiation of action potentials is in the axon. Here we use recordings from visualized rat cerebellar Purkinje cell axons to localize the site of initiation to a well-defined anatomical structure: the first node of Ranvier, which normally forms at the first axonal branch point.

The information efficacy of a synapse

We provide a functional measure, the synaptic information efficacy (SIE), to assess the impact of synaptic input on spike output. SIE is the mutual information shared by the presynaptic input and postsynaptic output spike trains. To estimate SIE we used a method based on compression algorithms. This method detects the effect of a single synaptic input on the postsynaptic spike output in the presence of massive background synaptic activity in neuron models of progressively increasing realism. SIE increased with increases either in time locking between the input synapse activity and the output spike or in the average number of output spikes. SIE depended on the context in which the synapse operates. We also measured SIE experimentally. Systematic exploration of the effect of synaptic and dendritic parameters on the SIE offers a fresh look at the synapse as a communication device and a quantitative measure of how much the dendritic synapse informs the axon.

Subthreshold Voltage Noise Due to Channel Fluctuations in Active Neuronal Membranes

Voltage-gated ion channels in neuronal membranes fluctuate randomly between different conformational states due to thermal agitation. Fluctuations between conducting and nonconducting states give rise to noisy membrane currents and subthreshold voltage fluctuations and may contribute to variability in spike timing. Here we study subthreshold voltage fluctuations due to active voltage-gated Na+ and K+ channels as predicted by two commonly used kinetic schemes: the Mainen et al. (1995) (MJHS) kinetic scheme, which has been used to model dendritic channels in cortical neurons, and the classical Hodgkin-Huxley (1952) (HH) kinetic scheme for the squid giant axon. We compute the magnitudes, amplitude distributions, and power spectral densities of the voltage noise in isopotential membrane patches predicted by these kinetic schemes. For both schemes, noise magnitudes increase rapidly with depolarization from rest. Noise is larger for smaller patch areas but is smaller for increased model temperatures. We contrast the results from Monte Carlo simulations of the stochastic nonlinear kinetic schemes with analytical, closed-form expressions derived using passive and quasi-active linear approximations to the kinetic schemes. For all subthreshold voltage ranges, the quasi-active linearized approximation is accurate within 8% and may thus be used in large-scale simulations of realistic neuronal geometries.

Tonic Inhibition Enhances Fidelity of Sensory Information Transmission in the Cerebellar Cortex

Tonic inhibition is a key regulator of neuronal excitability and network function in the brain, but its role in sensory information processing remains poorly understood. The cerebellum is a favorable model system for addressing this question as granule cells, which form the input layer of the cerebellar cortex, permit high-resolution patch-clamp recordings in vivo, and are the only neurons in the cerebellar cortex that express the α6δ-containing GABAA receptors mediating tonic inhibition. We investigated how tonic inhibition regulates sensory information transmission in the rat cerebellum by using a combination of intracellular recordings from granule cells and molecular layer interneurons in vivo, selective pharmacology, and in vitro dynamic clamp experiments. We show that blocking tonic inhibition significantly increases the spontaneous firing rate of granule cells while only moderately increasing sensory-evoked spike output. In contrast, enhancing tonic inhibition reduces the spike probability in response to sensory stimulation with minimal effect on the spontaneous spike rate. Both manipulations result in a reduction in the signal-to-noise ratio of sensory transmission in granule cells and of parallel fiber synaptic input to downstream molecular layer interneurons. These results suggest that under basal conditions the level of tonic inhibition in vivo enhances the fidelity of sensory information transmission through the input layer of the cerebellar cortex.

Local and Global Effects of Ih Distribution in Dendrites of Mammalian Neurons

The hyperpolarization-activated cation current Ih exhibits a steep gradient of channel density in dendrites of pyramidal neurons, which is associated with location independence of temporal summation of EPSPs at the soma. In striking contrast, here we show by using dendritic patch-clamp recordings that in cerebellar Purkinje cells, the principal neurons of the cerebellar cortex, Ih exhibits a uniform dendritic density, while location independence of EPSP summation is observed. Using compartmental modeling in realistic and simplified dendritic geometries, we demonstrate that the dendritic distribution of Ih only weakly affects the degree of temporal summation at the soma, while having an impact at the dendritic input location. We further analyze the effect of Ih on temporal summation using cable theory and derive bounds for temporal summation for any spatial distribution of Ih. We show that the total number of Ih channels, not their distribution, governs the degree of temporal summation of EPSPs. Our findings explain the effect of Ih on EPSP shape and temporal summation, and suggest that neurons are provided with two independent degrees of freedom for different functions: the total amount of Ih (controlling the degree of temporal summation of dendritic inputs at the soma) and the dendritic spatial distribution of Ih (regulating local dendritic processing).

Synaptic scaling in vitro and in vivo.

853 TO THE EDITOR—The recent study by Magee and Cook1 in CA1 pyramidal neurons in vitro (see also ref. 2) raises a fundamental issue. Is the dependence of somatic EPSPs on the location of the dendritic synapses, which is expected from dendritic filtering, a ‘bug’ that should be rectified (for example, by mechanisms that eliminate voltage attenuation in the dendritic tree), or is this dependence a ‘feature’ that enhances the computational capability of the neuron? Magee and Cook’s direct dendritic measurements show that the synaptic conductance change, gsyn, becomes larger as one moves along the apical dendrite, away from the soma. This progressive increase in gsyn counterbalances the voltage attenuation imposed by dendritic cable properties, and consequently, the amplitude of unitary somatic EPSPs is insensitive to its dendritic origin (‘location-independent’ somatic EPSPs). If the location dependence of soma EPSPs is indeed removed, then “...all synapses will have the same ability to initiate action potentials and to induce long-term synaptic plasticity regardless of their location in the dendritic arborization”1 and, functionally, the neuron could be treated as a ‘point neuron’. But is it valid to assume that if, in vitro, the size of individual somatic EPSPs is independent of the dendritic input location, this would also remain true when many synapses bombard the dendritic tree, as is the case in vivo? We show that in the latter case, the locationindependence found in the quiescent in vitro condition is lost, and distal synapses become weaker at the soma than do proximal synapses (Fig. 1; see web supplement, http://www.nature.com/neuro/ web_specials/, for detailed figure legend). This is the result of a several-fold increase in dendritic membrane conductance, Gm, due to the activity of many synapses in vivo3–6. In other words, precisely the same mechanism of synaptic conductance change that is used for scaling up distal synapses destroys the ‘location independence’ (it is ‘self defeating’) when the network is active. The general argument is that if, in some reference cases, the scaling of synaptic conductance gives rise to location-independent EPSP amplitude at the Synaptic scaling in vitro and in vivo

Tonic inhibition sets the state of excitability in olfactory bulb granule cells

•  Granule cells are the main source of inhibition in the olfactory bulb (i.e. the first station of odour processing in the mammalian brain), but very little is known about the inhibition that acts upon them. •  Using in vivo whole cell patch clamp recordings in anaesthetized mice we report the following new findings: •  We found odour‐evoked responses to be rare (seen only in 18% of the odour presentations, and only in cells that showed also evoked excitatory responses to odours). •  We report for the first time the presence of tonic inhibition in the olfactory bulb. •  We show that tonic inhibition dominates over phasic synaptic inhibition evoked by odours, thereby being the key regulator shaping the granule cells spike output. •  Preliminary (in vivo) evidence suggests that sensory evoked phasic inhibition onto granule cells is provided by deep short axon cells in the olfactory bulb.

Predicting the synaptic information efficacy in cortical layer 5 pyramidal neurons using a minimal integrate-and-fire model

Synaptic information efficacy (SIE) is a statistical measure to quantify the efficacy of a synapse. It measures how much information is gained, on the average, about the output spike train of a postsynaptic neuron if the input spike train is known. It is a particularly appropriate measure for assessing the input–output relationship of neurons receiving dynamic stimuli. Here, we compare the SIE of simulated synaptic inputs measured experimentally in layer 5 cortical pyramidal neurons in vitro with the SIE computed from a minimal model constructed to fit the recorded data. We show that even with a simple model that is far from perfect in predicting the precise timing of the output spikes of the real neuron, the SIE can still be accurately predicted. This arises from the ability of the model to predict output spikes influenced by the input more accurately than those driven by the background current. This indicates that in this context, some spikes may be more important than others. Lastly we demonstrate another aspect where using mutual information could be beneficial in evaluating the quality of a model, by measuring the mutual information between the model’s output and the neuron’s output. The SIE, thus, could be a useful tool for assessing the quality of models of single neurons in preserving input–output relationship, a property that becomes crucial when we start connecting these reduced models to construct complex realistic neuronal networks.

Long term beneficial effect of neurotrophic factors-secreting mesenchymal stem cells transplantation in the BTBR mouse model of autism

HighlightsMSC and NurOwn® treatments induced a long‐lasting effect of amelioration of autistic‐like behaviors.NurOwn® treatment had advantages over MSC treatment in terms of communication and stereotypic behavior.Both MSC and NurOwn® treatments induced a long‐lasting improvement in social behavior. Abstract Autism spectrum disorders (ASD) are neurodevelopmental disabilities characterized by severe impairment in social communication skills and restricted, repetitive behaviors. We have previously shown that a single transplantation of mesenchymal stem cells (MSC) into the cerebral lateral ventricles of BTBR autistic‐like mice resulted in an improvement across all diagnostic criteria of ASD. We suggested that brain‐derived neurotrophic factor (BDNF), a protein which supports the survival and regeneration of neurons secreted by MSC, largely contributed to the beneficial behavioral effect. In this study, we investigated the behavioral effects of transplanted MSC induced to secrete higher amounts of neurotrophic factors (NurOwn®), on various ASD‐related behavioral domains using the BTBR mouse model of ASD. We demonstrate that NurOwn® transplantation had significant advantages over MSC transplantation in terms of improving communication skills, one and six months following treatment, as compared to sham‐treated BTBR mice. Furthermore, NurOwn® transplantation resulted in reduced stereotypic behavior for as long as six months post treatment, compared to the one month improvement observed in the MSC treated mice. Notably, NurOwn® treatment resulted in improved cognitive flexibility, an improvement that was not observed by MSC treatment. Both MSC and NurOwn® transplantation induced an improvement in social behavior that lasted for six months. In conclusion, the present study demonstrates that a single transplantation of MSC or NurOwn® have long‐lasting benefits, while NurOwn® may be superior to MSC treatment.