Fast-spiking Parvalbumin Interneurons are Frequently Myelinated in the Cerebral Cortex of Mice and Humans

Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (~27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regulate synapse formation along PV interneuron axons. Taken together, fast-spiking interneuron myelination is likely to have broad implications for cerebral cortex function in health and disease

Distributed Network Actions by Nicotine Increase the Threshold for Spike-Timing-Dependent Plasticity in Prefrontal Cortex

SummaryNicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABAA receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP

Fast-spiking Parvalbumin Interneurons are Frequently Myelinated in the Cerebral Cortex of Mice and Humans

Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (∼27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regu

Fast-spiking Parvalbumin Interneurons are Frequently Myelinated in the Cerebral Cortex of Mice and Humans

Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (~27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regulate synapse formation along PV interneuron axons. Taken together, fast-spiking interneuron myelination is likely to have broad implications for cerebral cortex function in health and disease

An analysis of waves underlying grid cell firing in the medial enthorinal cortex

Layer II stellate cells in the medial enthorinal cortex (MEC) express hyperpolarisation-activated cyclic-nucleotide-gated (HCN) channels that allow for rebound spiking via an I_h current in response to hyperpolarising synaptic input. A computational modelling study by Hasselmo [2013 Neuronal rebound spiking, resonance frequency and theta cycle skipping may contribute to grid cell firing in medial entorhinal cortex. Phil. Trans. R. Soc. B 369: 20120523] showed that an inhibitory network of such cells can support periodic travelling waves with a period that is controlled by the dynamics of the I_h current. Hasselmo has suggested that these waves can underlie the generation of grid cells, and that the known difference in I_h resonance frequency along the dorsal to ventral axis can explain the observed size and spacing between grid cell firing fields. Here we develop a biophysical spiking model within a framework that allows for analytical tractability. We combine the simplicity of integrate-and-fire neurons with a piecewise linear caricature of the gating dynamics for HCN channels to develop a spiking neural field model of MEC. Using techniques primarily drawn from the field of nonsmooth dynamical systems we show how to construct periodic travelling waves, and in particular the dispersion curve that determines how wave speed varies as a function of period. This exhibits a wide range of long wavelength solutions, reinforcing the idea that rebound spiking is a candidate mechanism for generating grid cell firing patterns. Importantly we develop a wave stability analysis to show how the maximum allowed period is controlled by the dynamical properties of the I_h current. Our theoretical work is validated by numerical simulations of the spiking model in both one and two dimensions

Brief Bursts Self-Inhibit and Correlate the Pyramidal Network

A multi-cell patch clamp study reveals the summation properties of frequency-dependent disynaptic inhibition between neocortical pyramidal cells and shows how brief bursts of activity in a few cells can synchronize the entire microcircuit

Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit.This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder

Grid-like processing of imagined navigation

Grid cells in the entorhinal cortex (EC) of rodents [1] and humans [2] fire in a hexagonally distributed spatially periodic manner. In concert with other spatial cells in the medial temporal lobe (MTL) [3-6], they provide a representation of our location within an environment [7, 8] and are specifically thought to allow the represented location to be updated by self-motion [9]. Grid-like signals have been seen throughout the autobiographical memory system [10], suggesting a much more general role in memory [11, 12]. Grid cells may allow us to move our viewpoint in imagination [13], a useful function for goal-directed navigation and planning [12, 14-16], and episodic future thinking more generally [17, 18]. We used fMRI to provide evidence for similar grid-like signals in human entorhinal cortex during both virtual navigation and imagined navigation of the same paths. We show that this signal is present in periods of active navigation and imagination, with a similar orientation in both and with the specifically 6-fold rotational symmetry characteristic of grid cell firing. We therefore provide the first evidence suggesting that grid cells are utilized during movement of viewpoint within imagery, potentially underpinning our more general ability to mentally traverse possible routes in the service of planning and episodic future thinking