Apical Dendrites Research Articles

Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.

Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth.

Dendrite-Specific Amplification of Weak Synaptic Input during Network Activity In Vivo

SummaryExcitatory synaptic input reaches the soma of a cortical excitatory pyramidal neuron via anatomically segregated apical and basal dendrites. In vivo, dendritic inputs are integrated during depolarized network activity, but how network activity affects apical and basal inputs is not understood. Using subcellular two-photon stimulation of Channelrhodopsin2-expressing layer 2/3 pyramidal neurons in somatosensory cortex, nucleus-specific thalamic optogenetic stimulation, and paired recordings, we show that slow, depolarized network activity amplifies small-amplitude synaptic inputs targeted to basal dendrites but reduces the amplitude of all inputs from apical dendrites and the cell soma. Intracellular pharmacology and mathematical modeling suggests that the amplification of weak basal inputs is mediated by postsynaptic voltage-gated channels. Thus, network activity dynamically reconfigures the relative somatic contribution of apical and basal inputs and could act to enhance the detectability of weak synaptic inputs.

Anterolateral Motor Cortex Connects with a Medial Subdivision of Ventromedial Thalamus through Cell Type-Specific Circuits, Forming an Excitatory Thalamo-Cortico-Thalamic Loop via Layer 1 Apical Tuft Dendrites of Layer 5B Pyramidal Tract Type Neurons.

The anterolateral motor cortex (ALM) and ventral medial (VM) thalamus are functionally linked to support persistent activity during motor planning. We analyzed the underlying synaptic interconnections using optogenetics and electrophysiology in mice (female/male). In cortex, thalamocortical (TC) axons from VM thalamus excited VM-projecting pyramidal tract (PT) neurons in layer 5B of ALM. These axons also strongly excited layer 2/3 neurons (which strongly excite PT neurons, as previously shown) but not VM-projecting corticothalamic (CT) neurons in layer 6. The strongest connections in the VM → PT circuit were localized to apical tuft dendrites of PT neurons, in layer 1. These tuft inputs were selectively augmented after blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In thalamus, axons from ALM PT neurons excited ALM-projecting VM neurons, located medially in VM. These axons provided weak input to neurons in mediodorsal nucleus, and little or no input either to neurons in the GABAergic reticular thalamic nucleus or to neurons in VM projecting to primary motor cortex (M1). Conversely, M1 PT axons excited M1- but not ALM-projecting VM neurons. Our findings indicate, first, a set of cell type-specific connections forming an excitatory thalamo-cortico-thalamic loop for ALM ↔ VM communication and a circuit-level substrate for supporting reverberant activity in this system. Second, a key feature of this loop is the prominent involvement of layer 1 synapses onto apical dendrites, a subcellular compartment with distinct signaling properties, including HCN-mediated gain control. Third, the segregation of the ALM ↔ VM loop from M1-related circuits of VM adds cellular-level support for the concept of parallel pathway organization in the motor system.SIGNIFICANCE STATEMENT Anterolateral motor cortex (ALM), a higher-order motor area in the mouse, and ventromedial (VM) thalamus are anatomically and functionally linked, but their synaptic interconnections at the cellular level are unknown. Our results show that ALM pyramidal tract neurons monosynaptically excite ALM-projecting thalamocortical neurons in a medial subdivision of VM thalamus, and vice versa. The thalamo-cortico-thalamic loop formed by these recurrent connections constitutes a circuit-level substrate for supporting reverberant activity in this system.

Hippocampal Memory Recovery After Acute Stress: A Behavioral, Morphological and Molecular Study

Several studies have shown that a single exposure to stress may improve or impair learning and memory processes, depending on the timing in which the stress event occurs with relation to the acquisition phase. However, to date there is no information about the molecular changes that occur at the synapse during the stress-induced memory modification and after a recovery period. In particular, there are no studies that have evaluated—at the same time—the temporality of stress and stress recovery period in hippocampal short-term memory and the effects on dendritic spine morphology, along with variations in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. The aim of our study was to take a multidimensional approach to investigate concomitant behavioral, morphological and molecular changes induced by a single restraint stress exposure (2.5 h) and a recovery period of 6 and 24 h in rats. We found that acute stress elicited a reduced preference to explore an object placed in a novel position (a hippocampal-dependent task). These changes were accompanied by increased activity of LIM kinase I (LIMK; an actin-remodeling protein) and increased levels of NR2A subunits of NMDA receptors. After 6 h of recovery from stress, rats showed similar preference to explore an object placed in a novel or familiar position, but density of immature spines increased in secondary CA1 apical dendrites, along with a transient rise in GluA2 AMPA receptor subunits. After 24 h of recovery from stress, the animals showed a preference to explore an object placed in a novel position, which was accompanied by a normalization of NMDA and AMPA receptor subunits to control values. Our data suggest that acute stress produces reversible molecular and behavioral changes 24 h after stress, allowing a full reestablishment of hippocampal-related memory. Further studies need to be conducted to deepen our understanding of these changes and their reciprocal interactions.Adaptive stress responses are a promising avenue to develop interventions aiming at restoring hippocampal function impaired by repetitive stress exposure.

Differential dynamics of cortical neuron dendritic trees revealed by long-term in vivo imaging in neonates

Proper neuronal circuit function relies on precise dendritic projection, which is established through activity-dependent refinement during early postnatal development. Here we revealed dynamics of dendritic refinement in the mammalian brain by conducting long-term imaging of the neonatal mouse barrel cortex. By “retrospective” analyses, we identified “prospective” barrel-edge spiny stellate (SS) neurons in early neonates, which had an apical dendrite and primitive basal dendrites (BDs). These neurons retracted the apical dendrite gradually and established strong BD orientation bias through continuous “dendritic tree” turnover. A greater chance of survival was given to BD trees emerged in the barrel-center side, where thalamocortical axons (TCAs) cluster. When the spatial bias of TCA inputs to SS neurons was lost, BD tree turnover was suppressed, and most BD trees became stable and elaborated mildly. Thus, barrel-edge SS neurons could establish the characteristic BD projection pattern through differential dynamics of dendritic trees induced by spatially biased inputs.

Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluR in the Hippocampal CA1 Region

SummarySoluble Aβ oligomers (oAβs) contribute importantly to synaptotoxicity in Alzheimer disease (AD), but the mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Nearly all studies of the effects of oAβs on hippocampal synaptic plasticity have only examined homosynaptic plasticity. Here we stimulated the Schaffer collaterals and then simultaneously recorded in stratum radiatum (apical dendrites) and stratum oriens (basal dendrites) of CA1 neurons. We found that the apical dendrites are significantly more vulnerable to oAβ-mediated synaptic dysfunction: the heterosynaptic basal dendritic long-term potentiation (LTP) remained unchanged, whereas the homosynaptic apical LTP was impaired. However, the heterosynaptic basal dendritic plasticity induced by either spaced 10-Hz bursts or low-frequency (1-Hz) stimulation was disrupted by oAβs in a mGluR5-dependent manner. These results suggest that different firing patterns in the same neurons may be selectively altered by soluble oAβs in an early phase of AD, before frank neurodegeneration.

Loss of thin spines and small synapses contributes to defective hippocampal function in aged mice.

Aging is a normal physiological process associated with impairments in cognitive function, including learning and memory. Here, the underlying synaptic mechanisms by which aging leads to the decline of spatial learning and memory function were investigated in 25-month-old aged mice versus 2-month-old young mice. Deficits of spatial learning and memory, as well as selective loss of thin spines, but not mushroom-type spines on apical dendrites of CA1 pyramidal cells were found in aged mice. Specifically, loss of thin spines in aged mice with memory deficits was primarily found on dendritic segments located in the Schaffer pathway, and the density of thin spines significantly correlated with spatial memory performance. The loss of thin spines was evidenced by a decrease in small synapses that express diminutive amounts of postsynaptic density protein-95 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1. Furthermore, mushroom-type spines and GluR1-expressed large synapses were not affected in aged mice with impaired memory. Taken together, these data suggest that the selective loss of those highly plastic thin spines with sparse postsynaptic density protein-95 and GluR1 receptors may significantly contribute to cognitive deficits in aged individuals.

Effect of developmental lead exposure on neurogenesis and cortical neuronal morphology in Wistar rats

Lead (Pb) is a neurotoxic heavy metal that largely affects the developing nervous system. The present study examined the temporal effect of perinatal Pb exposure on neurogenesis and cortical neuronal morphology. Wistar pregnant rats were exposed to 0.5% lead acetate throughout pregnancy and to postnatal day (PD) 28. Offspring were grouped as gestational day (GD) 18 and 21 and PD 7, 14, 21, and 28 in both control and experimental groups. Brain sections were processed for immunohistological staining with anti-proliferating cell nuclear antigen (PCNA) or glial fibrillary acidic protein (GFAP). Brains from 14, 21, and 28 PDs pups were processed for Golgi-Cox stain. Pb exposure significantly increased PCNA-positive nuclei in the ventricular and subventricular zones of the lateral ventricle at 18 and 21 GDs. Postnatally, the Pb-treated groups showed a significant decrease in PCNA-positivity and neuron density compared to control. This reduction was associated with an increase in damaged or apoptotic cell profiles in the experimental groups. At PD 21, there was a significant increase in GFAP immunoreactivity in Pb-exposed groups compared with control. Furthermore, the total apical and basal dendritic length of pyramidal neurons in layer 2-3 of the Golgi-Cox stained sensorimotor cortex was comparable in both control and Pb-exposed groups. Spine density per 10 µm was significantly increased at PD 14 and 21 on the apical dendrites but not basal dendrites of Pb-treated groups. In conclusion, developmental Pb exposure in rats induces a toxic effect on neurogenesis and on cortical neurons, which may be related to cognitive disabilities observed in children exposed to lead.

A-type K+ channels impede supralinear summation of clustered glutamatergic inputs in layer 3 neocortical pyramidal neurons

A-type K+ channels restrain the spread of incoming signals in tufted and apical dendrites of pyramidal neurons resulting in strong compartmentalization. However, the exact subunit composition and functional significance of K+ channels expressed in small diameter proximal dendrites remain poorly understood. We focus on A-type K+ channels expressed in basal and oblique dendrites of cortical layer 3 pyramidal neurons, in ex vivo brain slices from young adult mice. Blocking putative Kv4 subunits with phrixotoxin-2 enhances depolarizing potentials elicited by uncaging RuBi-glutamate at single dendritic spines. A concentration of 4-aminopyridine reported to block Kv1 has no effect on such responses. 4-aminopyridine and phrixotoxin-2 increase supralinear summation of glutamatergic potentials evoked by synchronous activation of clustered spines. The effect of 4-aminopyridine on glutamate responses is simulated in a computational model where the dendritic A-type conductance is distributed homogeneously or in a linear density gradient. Thus, putative Kv4-containing channels depress excitatory inputs at single synapses. The additional recruitment of Kv1 subunits might require the synchronous activation of multiple inputs to regulate the gain of signal integration.

A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

Pyramidal neurons express rich repertoires of leucine-rich repeat (LRR)-containing adhesion molecules with similar synaptogenic activity in culture. The invivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.

MGluR5-dependent modulation of dendritic excitability in CA1 pyramidal neurons mediated by enhancement of persistent Na+ currents.

High-frequency stimulation (HFS) of the Schaffer collateral pathway activates metabotropic glutamate receptor 5 (mGluR5) signalling in the proximal apical dendrites of CA1 pyramidal neurons. The synaptic activation of mGluR5-mediated calcium signalling causes a significant increase in persistent sodium current (INa,P ) in the dendrites. Increased INa,P by HFS underlies potentiation of synaptic inputs at both the proximal and distal dendrite, leading to an enhanced probability of action potential firing associated with decreased action potential thresholds. Therefore, HFS-induced activation of intracellular mGluR5 serves an important role as an instructive signal for potentiation of upcoming inputs by increasing dendritic excitability. Dendritic Na+ channels in pyramidal neurons are known to amplify synaptic signals, thereby facilitating action potential (AP) generation. However, the mechanisms that modulate dendritic Na+ channels have remained largely uncharacterized. Here, we report a new form of short-term plasticity in which proximal excitatory synaptic inputs to hippocampal CA1 pyramidal neurons transiently elevate dendritic excitability. High-frequency stimulations (HFS) to the Schaffer collateral (SC) pathway activate mGluR5-dependent Ca2+ signalling in the apical dendrites, which, with calmodulin, upregulates specifically Nav1.6 channel-mediated persistent Na+ currents (INa,P ) in the dendrites. This HFS-induced increase in dendritic INa,P results in transient increases in the amplitude of excitatory postsynaptic potentials induced by both proximal SC and distal perforant path stimulation, leading to the enhanced probability of AP firing associated with decreased AP thresholds. Taken together, our study identifies dendritic INa,P as a novel target for mediating activity-dependent modulation of dendritic integration and neuronal output.

Modulation of Kalirin-7 expression by hippocampal CA1 5-HT1B receptors in spatial memory consolidation

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.

Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance

Bassoon is a large scaffolding protein of the presynaptic active zone involved in the development of presynaptic terminals and in the regulation of neurotransmitter release at both excitatory and inhibitory brain synapses. Mice with constitutive ablation of the Bassoon (Bsn) gene display impaired presynaptic function, show sensory deficits and develop severe seizures. To specifically study the role of Bassoon at excitatory forebrain synapses and its relevance for control of behavior, we generated conditional knockout (Bsn cKO) mice by gene ablation through an Emx1 promoter-driven Cre recombinase. In these animals, we confirm selective loss of Bassoon from glutamatergic neurons of the forebrain. Behavioral assessment revealed that, in comparison to wild-type littermates, Bsn cKO mice display selectively enhanced contextual fear memory and increased novelty preference in a spatial discrimination/pattern separation task. These changes are accompanied by an augmentation of baseline synaptic transmission at medial perforant path to dentate gyrus (DG) synapses, as indicated by increased ratios of field excitatory postsynaptic potential slope to fiber volley amplitude. At the structural level, an increased complexity of apical dendrites of DG granule cells can be detected in Bsn cKO mice. In addition, alterations in the expression of cellular maturation markers and a lack of age-dependent decrease in excitability between juvenile and adult Bsn cKO mice are observed. Our data suggest that expression of Bassoon in excitatory forebrain neurons is required for the normal maturation of the DG and important for spatial and contextual memory.

H-Type Membrane Current Shapes the Local Field Potential from Populations of Pyramidal Neurons.

In cortex, the local field potential (LFP) is thought to mainly stem from correlated synaptic input to populations of geometrically aligned neurons. Computer models of single cortical pyramidal neurons showed that subthreshold voltage-dependent membrane conductances can also shape the LFP signal, in particular the hyperpolarization-activated cation current (Ih; h-type). This ion channel is prominent in various types of pyramidal neurons, typically showing an increasing density gradient along the apical dendrites. Here, we investigate how Ih affects the LFP generated by a model of a population of cortical pyramidal neurons. We find that the LFP from populations of neurons that receive uncorrelated synaptic input can be well predicted by the LFP from single neurons. In this case, when input impinges on the distal dendrites, where most h-type channels are located, a strong resonance in the LFP was measured near the soma, whereas the opposite configuration does not reveal an Ih contribution to the LFP. Introducing correlations in the synaptic inputs to the pyramidal cells strongly amplifies the LFP, while maintaining the differential effects of Ih for distal dendritic versus perisomatic input. Previous theoretical work showed that input correlations do not amplify LFP power when neurons receive synaptic input uniformly across the cell. We find that this crucially depends on the membrane conductance distribution: the asymmetric distribution of Ih results in a strong amplification of the LFP when synaptic inputs to the cell population are correlated. In conclusion, we find that the h-type current is particularly suited to shape the LFP signal in cortical populations.SIGNIFICANCE STATEMENT The local field potential (LFP), the low-frequency part of extracellular potentials recorded in neural tissue, is often used for probing neural circuit activity. While the cortical LFP is thought to mainly reflect synaptic inputs onto pyramidal neurons, little is known about the role of subthreshold active conductances in shaping the LFP. By means of biophysical modeling we obtain a comprehensive, qualitative understanding of how LFPs generated by populations of cortical pyramidal neurons depend on active subthreshold currents, and identify the key importance of the h-type channel. Our results show that LFPs can give information about the active properties of neurons and that preferred frequencies in the LFP can result from those cellular properties instead of, for example, network dynamics.

Anodal transcranial direct current stimulation affects auditory cortex plasticity in normal-hearing and noise-exposed rats

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive tool capable to modulate cortical functions by affecting neuronal excitability and synaptic plasticity. ObjectiveHere we investigated the effects of anodal tDCS on auditory cortex (ACx) in normal-hearing rats and following a paradigm of noise-induced hearing loss (NIHL), that causes morphological alterations in ACx pyramidal neurons. MethodsMale rats exposed to intense pure tone (10 kHz) were subsequently subjected to unilateral anodal tDCS of ACx and changes in dendritic morphology and spines were assessed by Golgi-Cox staining 30 days after the onset of the acoustic trauma. Molecular and functional changes were investigated by Western immunoblotting, immunofluorescence experiments and electrophysiological recordings in brain slices. ResultsWe found that NIHL altered dendritic morphology by decreasing spine density, mostly in layer 2/3 pyramidal neurons. Interestingly, tDCS increased ACx spine density, targeting apical dendrites of layer 2/3 and 5/6 pyramidal neurons in rats with normal auditory function and both apical and basal arborizations in layer 2/3 of NIHL rats. Twenty-four hours after tDCS, Bdnf and synaptophysin levels in ACx increased both in normal-hearing and noise-exposed rats. Field recordings showed that basal synaptic transmission at layer 2/3 horizontal connections was significantly reduced in noise-exposed rats compared to normal-hearing animals and, notably, input-output curves of noise-exposed animals subjected to tDCS were similar to those of normal-hearing rats. ConclusionsOur findings provide novel evidence that anodal tDCS affects structural plasticity in the ACx suggesting that it might be beneficial in treating cortical alterations due to cochlear damage.

A Mixed-Signal Structured AdEx Neuron for Accelerated Neuromorphic Cores.

Here, we describe a multicompartment neuron circuit based on the adaptive-exponential I&F (AdEx) model, developed for the second-generation BrainScaleS hardware. Based on an existing modular leaky integrate-and-fire (LIF) architecture designed in 65-nm CMOS, the circuit features exponential spike generation, neuronal adaptation, intercompartmental connections as well as a conductance-based reset. The design reproduces a diverse set of firing patterns observed in cortical pyramidal neurons. Further, it enables the emulation of sodium and calcium spikes, as well as N-methyl-D-aspartate plateau potentials known from apical and thin dendrites. We characterize the AdEx circuit extensions and exemplify how the interplay between passive and nonlinear active signal processing enhances the computational capabilities of single (but structured) on-chip neurons.

Preferential stabilization of newly formed dendritic spines in motor cortex during manual skill learning predicts performance gains, but not memory endurance.

Previous findings that skill learning is associated with the formation and preferential stabilization of new dendritic spines in cortex have raised the possibility that this preferential stabilization is a mechanism for lasting skill memory. We investigated this possibility in adult mice using in vivo two-photon imaging to monitor spine dynamics on superficial apical dendrites of layer V pyramidal neurons in motor cortex during manual skill learning. Spine formation increased over the first 3 days of training on a skilled reaching task, followed by increased spine elimination. A greater proportion of spines formed during the first 3 training days were lost if training stopped after 3, compared with 15 days. However, performance gains achieved in 3 training days persisted, indicating that preferential new spine stabilization was non-essential for skill retention. Consistent with a role in ongoing skill refinement, the persistence of spines formed early in training strongly predicted performance improvements. Finally, while we observed no net spine density change on superficial dendrites, the density of spines on deeper apical branches of the same neuronal population was increased regardless of training duration, suggestive of a potential role in the retention of the initial skill memory. Together, these results indicate dendritic subpopulation-dependent variation in spine structural responses to skill learning, which potentially reflect distinct contributions to the refinement and retention of newly acquired motor skills.

Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice.

Retinoic acid (RA) and its receptors (RARs) are well established essential transcriptional regulators during embryonic development. Recent findings in cultured neurons identified an independent and critical post-transcriptional role of RA and RARα in the homeostatic regulation of excitatory and inhibitory synaptic transmission in mature neurons. However, the functional relevance of synaptic RA signaling in vivo has not been established. Here, using somatosensory cortex as a model system and the RARα conditional knock-out mouse as a tool, we applied multiple genetic manipulations to delete RARα postnatally in specific populations of cortical neurons, and asked whether synaptic RA signaling observed in cultured neurons is involved in cortical information processing in vivo Indeed, conditional ablation of RARα in mice via a CaMKIIα-Cre or a layer 5-Cre driver line or via somatosensory cortex-specific viral expression of Cre-recombinase impaired whisker-dependent texture discrimination, suggesting a critical requirement of RARα expression in L5 pyramidal neurons of somatosensory cortex for normal tactile sensory processing. Transcranial two-photon imaging revealed a significant increase in dendritic spine elimination on apical dendrites of somatosensory cortical layer 5 pyramidal neurons in these mice. Interestingly, the enhancement of spine elimination is whisker experience-dependent as whisker trimming rescued the spine elimination phenotype. Additionally, experiencing an enriched environment improved texture discrimination in RARα-deficient mice and reduced excessive spine pruning. Thus, RA signaling is essential for normal experience-dependent cortical circuit remodeling and sensory processing.SIGNIFICANCE STATEMENT The importance of synaptic RA signaling has been demonstrated in in vitro studies. However, whether RA signaling mediated by RARα contributes to neural circuit functions in vivo remains largely unknown. In this study, using a RARα conditional knock-out mouse, we performed multiple regional/cell-type-specific manipulation of RARα expression in the postnatal brain, and show that RARα signaling contributes to normal whisker-dependent texture discrimination as well as regulating spine dynamics of apical dendrites from layer (L5) pyramidal neurons in S1. Deletion of RARα in excitatory neurons in the forebrain induces elevated spine elimination and impaired sensory discrimination. Our study provides novel insights into the role of RARα signaling in cortical processing and experience-dependent spine maturation.

Differential polarization of cortical pyramidal neuron dendrites through weak extracellular fields

The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.

Resonance Analysis as a Tool for Characterizing Functional Division of Layer 5 Pyramidal Neurons.

Evidence suggests that layer 5 pyramidal neurons can be divided into functional zones with unique afferent connectivity and membrane characteristics that allow for post-synaptic integration of feedforward and feedback inputs. To assess the existence of these zones and their interaction, we characterized the resonance properties of a biophysically-realistic compartmental model of a neocortical layer 5 pyramidal neuron. Consistent with recently published theoretical and empirical findings, our model was configured to have a “hot zone” in distal apical dendrite and apical tuft where both high- and low-threshold Ca2+ ionic conductances had densities 1–2 orders of magnitude higher than anywhere else in the apical dendrite. We simulated injection of broad spectrum sinusoidal currents with linearly increasing frequency to calculate the input impedance of individual compartments, the transfer impedance between the soma and key compartments within the dendritic tree, and a dimensionless term we introduce called resonance quality. We show that input resonance analysis distinguished at least four distinct zones within the model based on properties of their frequency preferences: basal dendrite which displayed little resonance; soma/proximal apical dendrite which displayed resonance at 5–23 Hz, strongest at 5–10 Hz and hyperpolarized/resting membrane potentials; distal apical dendrite which displayed resonance at 8–19 Hz, strongest at 10 Hz and depolarized membrane potentials; and apical tuft which displayed a weak resonance largely between 8 and 10 Hz across a wide range of membrane potentials. Transfer resonance analysis revealed that changes in subthreshold electrical coupling were found to modulate the transfer resonant frequency of signals transmitted from distal apical dendrite and apical tuft to the soma, which would impact the frequencies that individual neurons are expected to respond to and reinforce. Furthermore, eliminating the hot zone was found to reduce amplification of resonance within the model, which contributes to reduced excitability when perisomatic and distal apical regions receive coincident stimulating current injections. These results indicate that the interactions between different functional zones should be considered in a more complete understanding of neuronal integration. Resonance analysis may therefore be a useful tool for assessing the integration of inputs across the entire neuronal membrane.