Spiny Dendrites Research Articles

Engineered neurogenesis in naïve adult rat cortex by Ngn2-mediated neuronal reprogramming of resident oligodendrocyte progenitor cells.

Adult tissue stem cells contribute to tissue homeostasis and repair but the long-lived neurons in the human adult cerebral cortex are not replaced, despite evidence for a limited regenerative response. However, the adult cortex contains a population of proliferating oligodendrocyte progenitor cells (OPCs). We examined the capacity of rat cortical OPCs to be re-specified to a neuronal lineage both in vitro and in vivo. Expressing the developmental transcription factor Neurogenin2 (Ngn2) in OPCs isolated from adult rat cortex resulted in their expression of early neuronal lineage markers and genes while downregulating expression of OPC markers and genes. Ngn2 induced progression through a neuronal lineage to express mature neuronal markers and functional activity as glutamatergic neurons. In vivo retroviral gene delivery of Ngn2 to naive adult rat cortex ensured restricted targeting to proliferating OPCs. Ngn2 expression in OPCs resulted in their lineage re-specification and transition through an immature neuronal morphology into mature pyramidal cortical neurons with spiny dendrites, axons, synaptic contacts, and subtype specification matching local cytoarchitecture. Lineage re-specification of rat cortical OPCs occurred without prior injury, demonstrating these glial progenitor cells need not be put into a reactive state to achieve lineage reprogramming. These results show it may be feasible to precisely engineer additional neurons directly in adult cerebral cortex for experimental study or potentially for therapeutic use to modify dysfunctional or damaged circuitry.

NMDA Receptor Antagonist MK801 Reduces Dendritic Spine Density and Stability in Zebrafish Pyramidal Neurons

NMDA-type glutamate receptors play a critical role in activity-dependent neurite growth. We employed cell type-specific genetic labeling in zebrafish to examine the effects of NMDA receptor antagonism on the morphological development of tectal pyramidal neurons (PyrNs). Our data demonstrate that the NMDA receptor antagonist MK801 reduces PyrN spine density and stability without significantly altering dendritic growth and branching. However, the axons that synapse onto PyrN dendritic spines do exhibit reduced arbor growth and branching in response to MK801 treatment. Axons that synapse with PyrNs, but not on spines, are unaffected by MK801 treatment. These findings may reflect different roles for NMDARs during the development of spiny and aspiny dendrites.

Numerical simulation using the non-standard weighted average FDM for 2Dim variable-order Cable equation

The fractional variable-order (VO) two-dimensional (2Dim) Cable equation is one of the most significant types of anomalous subdiffusion equations that emerge strongly in spiny neural dendrites and is solved by using an accurate numerical technique in this study. The non-standard weighted average finite difference approach is a simple proposed technique (NSWAFDM). The proposed method’s stability is investigated in depth by using the John von Neumann stability analysis approach. The arbitrary weight factor and multiple discretization schemes of the VO derivative are used to develop a specific stability criterion. To demonstrate the usefulness and accuracy of the suggested technique, numerical examples are offered.

Partial connectomes of labeled dopaminergic circuits reveal non-synaptic communication and axonal remodeling after exposure to cocaine.

Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change with drug exposure remains poorly understood. We leverage cell type-specific labeling with large volume serial electron microscopy to detail DA connections in the nucleus accumbens (NAc) of the mouse (Mus musculus) before and after exposure to cocaine. We find that individual DA axons contain different varicosity types based on their vesicle contents. Spatially ordering along individual axons further suggests that varicosity types are non-randomly organized. DA axon varicosities rarely make specific synapses (<2%, 6/410), but instead are more likely to form spinule-like structures (15%, 61/410) with neighboring neurons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls, formed blind-ended 'bulbs' filled with mitochondria, and were surrounded by elaborated glia. Finally, mitochondrial lengths increased by ~2.2 times relative to control only in DA axons and NAc spiny dendrites after cocaine exposure. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large-scale axonal re-arrangements with correlated changes in mitochondria.

Modeling multiple anomalous diffusion behaviors on comb-like structures

In this work, a generalized comb model which includes the memory kernels and linear reactions with irreversible and reversible parts are introduced to describe complex anomalous diffusion behavior. The probability density function (PDF) and the mean squared displacement (MSD) are obtained by analytical methods. Three different physical models are studied according to different reaction processes. When no reactions take place, we extend the diffusion process in 1-D under stochastic resetting to the N-D comb-like structures with backbone resetting and global resetting by using physically derived memory kernels. We find that the two different resetting ways only affect the asymptotic behavior of MSD in the long time. For the irreversible reaction, we obtain memory kernels based on experimental evidence of the transport of inert particles in spiny dendrites and explore the front propagation of CaMKII along dendrites. The reversible reaction plays an important role in the intermediate time, but the asymptotic behavior of MSD is the same with that in case of no reaction terms. The proposed reaction-diffusion model on the comb structure provides a generalized method for further study of various anomalous diffusion problems.

An ultrastructural connectomic analysis of a higher-order thalamocortical circuit in the mouse.

Many studies exist of thalamocortical synapses in primary sensory cortex, but much less in known about higher-order thalamocortical projections to higher-order cortical areas. We begin to address this gap using genetic labeling combined with large volume serial electron microscopy (i.e., "connectomics") to study the projection from the thalamic posterior medial nucleus to the secondary somatosensory cortex in a mouse. We injected into this thalamic nucleus a cocktail combining a cre-expressing virus and one expressing cre-dependent ascorbate peroxidase that provides an electron dense cytoplasmic label. This "intersectional" viral approach specifically labeled thalamocortical axons and synapses, free of retrograde labeling, in all layers of cortex. Labeled thalamocortical synapses represented 14% of all synapses in the cortical volume, consistent with previous estimates of first-order thalamocortical inputs. We found that labeled thalamocortical terminals, relative to unlabeled ones: were larger, were more likely to contain a mitochondrion, more frequently targeted spiny dendrites and avoided aspiny dendrites, and often innervated larger spines with spine apparatuses, among other differences. Furthermore, labeled terminals were more prevalent in layers 2/3 and synaptic differences between labeled and unlabeled terminals were greatest in layers 2/3. The laminar differences reported here contrast with reports of first-order thalamocortical connections in primary sensory cortices where, for example, labeled terminals were larger in layer 4 than layers 2/3 (Viaene et al., 2011a). These data offer the first glimpse of higher-order thalamocortical synaptic ultrastructure and point to the need for more analyses, as such connectivity likely represents a majority of thalamocortical circuitry.

Dendritic coincidence detection in Purkinje neurons of awake mice.

Dendritic coincidence detection is fundamental to neuronal processing yet remains largely unexplored in awake animals. Specifically, the underlying dendritic voltage-calcium relationship has not been directly addressed. Here, using simultaneous voltage and calcium two-photon imaging of Purkinje neuron spiny dendrites, we show how coincident synaptic inputs and resulting dendritic spikes modulate dendritic calcium signaling during sensory stimulation in awake mice. Sensory stimulation increased the rate of postsynaptic potentials and dendritic calcium spikes evoked by climbing fiber and parallel fiber synaptic input. These inputs are integrated in a time-dependent and nonlinear fashion to enhance the sensory-evoked dendritic calcium signal. Intrinsic supralinear dendritic mechanisms, including voltage-gated calcium channels and metabotropic glutamate receptors, are recruited cooperatively to expand the dynamic range of sensory-evoked dendritic calcium signals. This establishes how dendrites can use multiple interplaying mechanisms to perform coincidence detection, as a fundamental and ongoing feature of dendritic integration in behaving animals.

The double fractional Cattaneo model on anomalous transport of compounds in spiny dendrites structure

The double fractional Cattaneo model is first introduced to simulate the anomalous transport of inert compounds in spiny dendrites comb structure. Formulated governing equations with relaxation parameter are solved by Laplace transform and Mellin transform methods. The particle distribution and mean square displacement (MSD) are represented by Fox H-function and Mittag-Leffler function, respectively. We find that MSD has many forms, which can be used to describe complex diffusion in spiny dendrites problems. Considering the application in spinous dendrites, qualitative simulations are made and the physical significance of fractional parameters and delay parameters are obtained. Fractional parameter β represents the density of dendritic spines and relaxation parameter τ reflects the velocity of reaching spines. Besides, the effects of the fractional parameters and relaxation parameter on dynamic characteristics are graphically analyzed and discussed.

Dendritic and Spine Heterogeneity of von Economo Neurons in the Human Cingulate Cortex.

The human cingulate cortex (CC), included in the paralimbic cortex, participates in emotion, visceral responses, attention, cognition, and social behaviors. The CC has spindle-shaped/fusiform cell body neurons in its layer V, the von Economo neurons (VENs). VENs have further developed in primates, and the characterization of human VENs can benefit from the detailed descriptions of the shape of dendrites and spines. Here, we advance this issue and studied VENs in the anterior and midcingulate cortex from four neurologically normal adult subjects. We used the thionin technique and the adapted “single-section” Golgi method for light microscopy. Three-dimensional (3D) reconstructions were carried out for the visualization of Golgi-impregnated VENs’ cell body, ascending and descending dendrites, and collateral branches. We also looked for the presence, density, and shape of spines from proximal to distal dendrites. These neurons have a similar aspect for the soma, but features of spiny dendrites evidenced a morphological heterogeneity of CC VENs. Only for the description of this continuum of shapes, we labeled the most common feature as VEN 1, which has main dendritic shafts but few branches and sparse spines. VEN 2 shows an intermediate aspect, whereas VEN 3 displays the most profuse dendritic ramification and more spines with varied shapes from proximal to distal branches. Morphometric data exemplify the dendritic features of these cells. The heterogeneity of the dendritic architecture and spines suggests additional functional implications for the synaptic and information processing in VENs in integrated networks of normal and, possibly, neurological/psychiatric conditions involving the human CC.

Amygdalar Plasticity in Airway Disease

Asthma is one of the most common immunological diseases among humans. Chronic airway inflammation drives asthma pathophysiology. While much effort has focused on understanding the airway intrinsic effects of inflammation, chronic inflammation also activates stress‐responsive brain regions, including the amygdala. This is important because greater amygdala activity exaggerates inflammatory responses, and greater amygdala activation in asthmatic patients correlates with reduced bronchodilator responses. Within the amygdala, pyramidal neurons of the basolateral amygdala (BLA) encode aversive stimuli. These neurons are characterized by spiny dendrites, are excitatory (e.g., glutamatergic), and exhibit unique cellular and structural plasticity in response to aversive stimuli that is mechanistically linked to BLA function. Thus, pyramidal neurons might be key targets of inflammation that further drive asthma pathology. Here we test the central hypothesis that pyramidal neurons of the BLA encode airway inflammation and exacerbate asthma pathophysiology. Our preliminary data suggest that an acute asthma exacerbation increases activity of the murine BLA, as evidenced by c‐fos expression and manganese‐enhanced MRI. Further, we show that global pharmacological disruption of glutamatergic signaling mitigates airway disease features, including airway hyperreactivity and mucus hypersecretion. Finally, we show that airway inflammation increases dendritic spine density in pyramidal neurons of the BLA. These results identify novel therapeutic targets for asthma, and possibly other airway diseases.

Self-similar network model for fractional-order neuronal spiking: implications of dendritic spine functions

Fractional-order derivatives have been widely used to describe the spiking patterns of neurons, without considering their self-similar dendritic structures. In this study, a self-similar resistor–capacitor network is proposed to relate the spiny dendritic structure with fractional spiking properties. In order to achieve this goal, two types of networks comprising recursively staggered resistors and capacitors were developed to model the functional properties of smooth and spiny dendrites, respectively. Their overall electrotonic properties can be described by fractional order temporal operators derived by Heaviside operational calculus. According to this operator method, spiking patterns of spiny dendrites were controlled by the standard 0.5-order derivative, whereas an exponential modulation term was added in the governing fractional operator of the smooth dendrites. The application of these fractional operators in a leaky integrate-and-fire model reveals that the dendritic spine plays an important role in alternations of the spiking properties, including first-spike latency, firing rate adaptation, and afterhyperpolarization conductance. Further, the multilevel assembly of this network indicates that the fractional spiking behaviors of spiny neurons might originate from their hierarchical substructures, thereby highlighting possible functional consequences of alterations to dendritic self-similarity.

A simple numerical method for two‐dimensional nonlinear fractional anomalous sub‐diffusion equations

Recently, many numerical techniques were presented to solve the fractional anomalous sub‐diffusion equations, and the results were excellent. In this paper, we study a simple numerical technique to solve two important types of fractional anomalous sub‐diffusion equations that appear strongly in chemical reactions and spiny neuronal dendrites, which are the two‐dimensional fractional Cable equation and the two‐dimensional fractional reaction sub‐diffusion equation. The proposed technique is a simple one which is an extension of the weighted average finite difference technique. The stability analysis of the proposed method is studied by means of John von Neumann stability analysis technique. An accurate stability criterion which is valid for different discretization schemes of the fractional derivative and arbitrary weight factor is introduced. Four numerical examples are presented (two for the Cable equation and two for the reaction sub‐diffusion equation) to demonstrate the effectiveness and the accuracy of the presented method.

Novel long-range inhibitory nNOS-expressing hippocampal cells.

The hippocampus, a brain region that is important for spatial navigation and episodic memory, benefits from a rich diversity of neuronal cell-types. Through the use of an intersectional genetic viral vector approach in mice, we report novel hippocampal neurons which we refer to as LINCs, as they are long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells. LINCs project to several extrahippocampal regions including the tenia tecta, diagonal band, and retromammillary nucleus, but also broadly target local CA1 cells. LINCs are thus both interneurons and projection neurons. LINCs display regular spiking non-pyramidal firing patterns, are primarily located in the stratum oriens or pyramidale, have sparsely spiny dendrites, and do not typically express somatostatin, VIP, or the muscarinic acetylcholine receptor M2. We further demonstrate that LINCs can strongly influence hippocampal function and oscillations, including interregional coherence. The identification and characterization of these novel cells advances our basic understanding of both hippocampal circuitry and neuronal diversity.

Simultaneous dendritic voltage and calcium imaging and somatic recording from Purkinje neurons in awake mice

Spatiotemporal maps of dendritic signalling and their relationship with somatic output is fundamental to neuronal information processing, yet remain unexplored in awake animals. Here, we combine simultaneous sub-millisecond voltage and calcium two-photon imaging from distal spiny dendrites, with somatic electrical recording from spontaneously active cerebellar Purkinje neurons (PN) in awake mice. We detect discrete 1−2 ms suprathreshold voltage spikelets in the distal spiny dendrites during dendritic complex spikes. Spikelets and their calcium correlates are highly heterogeneous in number, timing and spatial distribution within and between complex spikes. Back-propagating simple spikes are highly attenuated. Highly variable 5–10 ms voltage hotspots are localized to fine dendritic processes and are reduced in size and frequency by lidocaine and CNQX. Hotspots correlated with somatic output but also, at high frequency, trigger purely dendritic calcium spikes. Summarizing, spatiotemporal signalling in PNs is far more complex, dynamic, and fine scaled than anticipated, even in resting animals.

Emergence of Fractional Kinetics in Spiny Dendrites

Fractional extensions of the cable equation have been proposed in the literature to describe transmembrane potential in spiny dendrites. The anomalous behavior has been related in the literature to the geometrical properties of the system, in particular, the density of spines, by experiments, computer simulations, and in comb-like models. The same PDE can be related to more than one stochastic process leading to anomalous diffusion behavior. The time-fractional diffusion equation can be associated to a continuous time random walk (CTRW) with power-law waiting time probability or to a special case of the Erdély-Kober fractional diffusion, described by the ggBm. In this work, we show that time fractional generalization of the cable equation arises naturally in the CTRW by considering a superposition of Markovian processes and in a ggBm-like construction of the random variable.

Structural and molecular heterogeneity of calretinin-expressing interneurons in the rodent and primate striatum.

Calretinin‐expressing (CR+) interneurons are the most common type of striatal interneuron in primates. However, because CR+ interneurons are relatively scarce in rodent striatum, little is known about their molecular and other properties, and they are typically excluded from models of striatal circuitry. Moreover, CR+ interneurons are often treated in models as a single homogenous population, despite previous descriptions of their heterogeneous structures and spatial distributions in rodents and primates. Here, we demonstrate that, in rodents, the combinatorial expression of secretagogin (Scgn), specificity protein 8 (SP8) and/or LIM homeobox protein 7 (Lhx7) separates striatal CR+ interneurons into three structurally and topographically distinct cell populations. The CR+/Scgn+/SP8+/Lhx7− interneurons are small‐sized (typically 7–11 µm in somatic diameter), possess tortuous, partially spiny dendrites, and are rostrally biased in their positioning within striatum. The CR+/Scgn−/SP8−/Lhx7− interneurons are medium‐sized (typically 12–15 µm), have bipolar dendrites, and are homogenously distributed throughout striatum. The CR+/Scgn−/SP8−/Lhx7+ interneurons are relatively large‐sized (typically 12–20 µm), and have thick, infrequently branching dendrites. Furthermore, we provide the first in vivo electrophysiological recordings of identified CR+ interneurons, all of which were the CR+/Scgn−/SP8−/Lhx7− cell type. In the primate striatum, Scgn co‐expression also identified a topographically distinct CR+ interneuron population with a rostral bias similar to that seen in both rats and mice. Taken together, these results suggest that striatal CR+ interneurons comprise at least three molecularly, structurally, and topographically distinct cell populations in rodents. These properties are partially conserved in primates, in which the relative abundance of CR+ interneurons suggests that they play a critical role in striatal microcircuits.

Translaminar circuits formed by the pyramidal cells in the superficial layers of cat visual cortex

Pyramidal cells in the superficial layers of the neocortex provide a major excitatory projection to layer 5, which contains the pyramidal cells that project to subcortical motor-related targets. Both structurally and functionally rather little is known about this interlaminar pathway, especially in higher mammals. Here, we made sparse ultrastructural reconstructions of the projection to layer 5 of three pyramidal neurons from layer 3 in cat V1 whose morphology, physiology, and synaptic connections with layers 2 and 3 were known. The dominant targets of the 74 identified synapses in layer 5 were the dendritic spines of pyramidal cells. The fractions of target spiny dendrites were 59, 61, and 84% for the three cells, with the remaining targets being dendrites of smooth neurons. These fractions were similar to the distribution of targets of unlabeled asymmetric synapses in the surrounding neuropil. Serial section reconstructions revealed that the target dendrites were heterogenous in morphology, indicating that different cell types are innervated. This new evidence indicates that the descending projection from the superficial layer pyramidal cells does not simply drive the output pyramidal cells that project to cortical and subcortical targets, but participates in the complex circuitry of the deep cortical layers.

Time fractional cable equation and applications in neurophysiology

We propose an extension of the cable equation by introducing a Caputo time fractional derivative. The fundamental solutions of the most common boundary problems are derived analytically via Laplace Transform, and result be written in terms of known special functions. This generalization could be useful to describe anomalous diffusion phenomena with leakage as signal conduction in spiny dendrites. The presented solutions are computed in Matlab and plotted.

An Ultrastructural Study of the Thalamic Input to Layer 4 of Primary Motor and Primary Somatosensory Cortex in the Mouse.

The traditional classification of primary motor cortex (M1) as an agranular area has been challenged recently when a functional layer 4 (L4) was reported in M1. L4 is the principal target for thalamic input in sensory areas, which raises the question of how thalamocortical synapses formed in M1 in the mouse compare with those in neighboring sensory cortex (S1). We identified thalamic boutons by their immunoreactivity for the vesicular glutamate transporter 2 (VGluT2) and performed unbiased disector counts from electron micrographs. We discovered that the thalamus contributed proportionately only half as many synapses to the local circuitry of L4 in M1 compared with S1. Furthermore, thalamic boutons in M1 targeted spiny dendrites exclusively, whereas ∼9% of synapses were formed with dendrites of smooth neurons in S1. VGluT2+ boutons in M1 were smaller and formed fewer synapses per bouton on average (1.3 vs 2.1) than those in S1, but VGluT2+ synapses in M1 were larger than in S1 (median postsynaptic density areas of 0.064 μm2 vs 0.042 μm2). In M1 and S1, thalamic synapses formed only a small fraction (12.1% and 17.2%, respectively) of all of the asymmetric synapses in L4. The functional role of the thalamic input to L4 in M1 has largely been neglected, but our data suggest that, as in S1, the thalamic input is amplified by the recurrent excitatory connections of the L4 circuits. The lack of direct thalamic input to inhibitory neurons in M1 may indicate temporal differences in the inhibitory gating in L4 of M1 versus S1.SIGNIFICANCE STATEMENT Classical interpretations of the function of primary motor cortex (M1) emphasize its lack of the granular layer 4 (L4) typical of sensory cortices. However, we show here that, like sensory cortex (S1), mouse M1 also has the canonical circuit motif of a core thalamic input to the middle cortical layer and that thalamocortical synapses form a small fraction (M1: 12%; S1: 17%) of all asymmetric synapses in L4 of both areas. Amplification of thalamic input by recurrent local circuits is thus likely to be a significant mechanism in both areas. Unlike M1, where thalamocortical boutons typically form a single synapse, thalamocortical boutons in S1 usually formed multiple synapses, which means they can be identified with high probability in the electron microscope without specific labeling.

Holding visual attention for 400 million years: A model of tectum and torus longitudinalis in teleost fishes

Only ray-finned fishes possess a torus longitudinalis (TL), a paired, elongated body attached to the medial margins of the optic tectum. Its granule cells project large numbers of fine fibers running laterally over adjacent tectum, synapsing excitatorily on the spiny dendrites of pyramidal cells. Sustained TL activity is evoked visuotopically by dark stimuli; TL bursting is a corollary discharge of saccadic eye movements. To suggest a function for this ancient structure, neural network models were constructed to show that: (1) pyramidal cells could form an attentional locus, selecting one out of several moving objects to track, but rapid image shifts caused by saccades disrupt tracking; (2) TL could supply both the pre-saccade position of a locus, and the shift predicted from a saccade so as to prime pyramidal dendrites at the target location, ensuring the locus stays with the attended object; (3) that the specific pattern of synaptic connections required for such predictive priming could be learned by an unsupervised rule; (4) temporal and spatial filtering of visual pattern input to TL allows learning from a complex scene. The principles thus evinced could apply to trans-saccadic attention and visual stability in other species.