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Annals of Anatomy = Anatomischer... Jan 2017Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its...
Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its neuroprotective and neurotrophic properties. This study used modern stereological techniques to investigate possible CA1 pyramidal neuron loss in 11-month-old triple transgenic AD (3xTg-AD) mice, and also the effects of therapeutic and subtherapeutic lithium doses on the number and density of CA1 pyramidal neurons and volume of CA1 pyramidal layer in 3xTg-AD and wild-type mice treated from 3 to 11 months of age. 3xTg-AD mice displayed CA1 pyramidal layer atrophy that is likely due to reduced neuronal volume because of the absence of neuronal loss. Both lithium treatments of 3xTg-AD mice, which already expressed AD-like pathology, had no effect on CA1 atrophy. However, lithium treatment of wild-type mice, at low (subtherapeutic) doses, induced a significant increase in total CA1 pyramidal neuron number that led to a significant increase in total CA1 pyramidal layer volume. The lithium-induced increase in CA1 neuron number is highly consistent with previous evidence that adult neurogenesis can be exogenously induced in the CA1 pyramidal layer with impact on total CA1 neuron number, thus raising the possibility of the chronic use of low-dose lithium as a strategy to help compensate for neuronal loss in CA1 and perhaps other typically non-neurogenic brain regions in various neurological diseases. With regard to AD, low-dose lithium intervention must be initiated as early as possible in the course of neuropathology for beneficial effects to occur.
Topics: Alzheimer Disease; Anatomy, Cross-Sectional; Animals; CA1 Region, Hippocampal; Cell Count; Dose-Response Relationship, Drug; Imaging, Three-Dimensional; Lithium Compounds; Male; Mice; Mice, Transgenic; Neuroprotective Agents; Pyramidal Cells; Treatment Outcome
PubMed: 27777112
DOI: 10.1016/j.aanat.2016.10.002 -
PLoS Computational Biology Sep 2022Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are...
Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation. We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal part of the apical dendrite and Ih-inhibiting modulation at the distal part of the apical dendrite can increase the layer V pyramidal excitability more than either of the two alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.
Topics: Action Potentials; Calcium; Cyclic Nucleotide-Gated Cation Channels; Dendrites; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Nucleotides, Cyclic; Pyramidal Cells
PubMed: 36099307
DOI: 10.1371/journal.pcbi.1010506 -
Neuron Mar 2022The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between...
The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between SWRs and hippocampal plasticity, little is known about how network state affects information processing in dendrites, the primary sites of synaptic input integration and plasticity. Here, we monitored somatic and basal dendritic activity in CA1 pyramidal cells in behaving mice using longitudinal two-photon calcium imaging integrated with simultaneous local field potential recordings. We found immobility was associated with an increase in dendritic activity concentrated during SWRs. Coincident dendritic and somatic activity during SWRs predicted increased coupling during subsequent exploration of a novel environment. In contrast, somatic-dendritic coupling and SWR recruitment varied with cells' tuning distance to reward location during a goal-learning task. Our results connect SWRs with the stabilization of information processing within CA1 neurons and suggest that these mechanisms may be dynamically biased by behavioral demands.
Topics: Animals; CA1 Region, Hippocampal; Hippocampus; Memory Consolidation; Mice; Neurons; Pyramidal Cells
PubMed: 35041805
DOI: 10.1016/j.neuron.2021.12.017 -
PloS One 2017Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified...
Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of ε2 subunits, we previously found that β2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB), an MHCI receptor. As in β2-microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry.
Topics: Animals; Dendritic Spines; Excitatory Postsynaptic Potentials; Functional Laterality; Gene Targeting; Hippocampus; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Nerve Net; Neuronal Plasticity; Phenols; Piperidines; Pyramidal Cells; Receptors, Immunologic; Synapses; Synaptic Transmission; beta 2-Microglobulin
PubMed: 28594961
DOI: 10.1371/journal.pone.0179377 -
ENeuro 2019Anatomical methods for determining cell type-specific connectivity are essential to inspire and constrain our understanding of neural circuit function. We developed...
Anatomical methods for determining cell type-specific connectivity are essential to inspire and constrain our understanding of neural circuit function. We developed genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue, using a fluorogen-activating protein (FAP)-coupled or YFP-coupled, postsynaptically-localized neuroligin-1 (NL-1) targeting sequence (FAP/YFPpost). FAPpost expression did not alter mEPSC or mIPSC properties. Sparse AAV-mediated expression of FAP/YFPpost with the cell-filling, red fluorophore dTomato (dTom) enabled high-throughput, compartment-specific detection of putative synapses across diverse neuron types in mouse somatosensory cortex. We took advantage of the bright, far-red emission of FAPpost puncta for multichannel fluorescence alignment of dendrites, FAPpost puncta, and presynaptic neurites in transgenic mice with saturated labeling of parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP)-expressing neurons using Cre-reporter driven expression of YFP. Subtype-specific inhibitory connectivity onto layer 2/3 (L2/3) neocortical pyramidal (Pyr) neurons was assessed using automated puncta detection and neurite apposition. Quantitative and compartment-specific comparisons show that PV inputs are the predominant source of inhibition at both the soma and the dendrites and were particularly concentrated at the primary apical dendrite. SST inputs were interleaved with PV inputs at all secondary-order and higher-order dendritic branches. These fluorescence-based synapse labeling reagents can facilitate large-scale and cell-type specific quantitation of changes in synaptic connectivity across development, learning, and disease states.
Topics: Animals; Connectome; Female; Fluorescent Dyes; High-Throughput Screening Assays; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optical Imaging; Pyramidal Cells; Somatosensory Cortex; Synapses
PubMed: 31548370
DOI: 10.1523/ENEURO.0193-19.2019 -
The Journal of Neuroscience : the... Jun 2019Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a...
Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a limited number of cells that participate in multiple cliques. The principles by which such cliques organize to encode information remain poorly understood. Similarly tuned pyramidal cells that preferentially target each other may form multicellular encoding units performing distinct computational tasks. The existence of such units can reflect upon both spontaneous and stimulus-driven population events.We applied two-photon calcium imaging to study spontaneous population bursts in layer 2/3 of area V1 in male C57BL/6 mice. To identify potential small-world cliques, we searched for pyramidal cells whose calcium events had a consistent temporal relationship with the events of local inhibitory interneurons. This was guided by the intuition that groups of neurons whose synchronous firing represents a temporally coherent computational unit should be inhibited together. Pyramidal members of these interneuron-centered clusters on average displayed stronger functional connectivity between each other than with nonmember pyramidal neurons. The structure of the clusters evolved during postnatal development: cluster size and overlap between clusters decreased with developmental maturation. Pyramidal neurons in a cluster showed higher than chance tuning function similarity between each other and with the linked interneuron. Thus, spontaneous population events in V1 are shaped by small-world subnetworks of pyramidal neurons that share functional properties and work as a coherent unit with a local interneuron. These interneuron-pyramidal cell partnerships may represent a fundamental neocortical unit of computation at the population level. Neuronal circuit in layer 2/3 of mouse area V1 possesses small-world network architecture, where cliques of densely interconnected neurons ("small worlds") communicate via restricted number of hub cells. We show that: (1) in mouse V1 individual small-world cliques preferably incorporate pyramidal neurons with similar visual feature tuning, and (2) ongoing population activity of such pyramidal neuron clique is temporally linked to the activity of the local interneuron sharing its feature tuning with the clique members. Functional grouping of similarly tuned interneurons and pyramidal cells into cliques may ensure that ensembles of functionally alike pyramidal cells recruited during perceptual tasks and spontaneous activity are also turned off together as a unit, with interneurons serving as organizers of linked pyramidal ensemble activity.
Topics: Action Potentials; Animals; Interneurons; Male; Mice; Nerve Net; Neurons; Optical Imaging; Photic Stimulation; Pyramidal Cells; Visual Cortex
PubMed: 30979814
DOI: 10.1523/JNEUROSCI.2275-18.2019 -
Journal of Neurophysiology Feb 2021Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex...
Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca concentration. Here, we use ratiometric Na imaging to demonstrate spontaneous fluctuations in the intracellular Na concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at (P2-4). These occur at very low frequency (∼2/h), can last minutes with amplitudes up to several millimolar, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Both our experiments and computational model show that blocking voltage-gated Na channels or GABAergic signaling significantly diminish the neuronal Na fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways does not have significant effects. Our model also shows that the amplitude and duration of Na fluctuations decrease as we increase the strength of glial K uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared with mature brain. Spontaneous activity in the neonate forebrain plays a key role in cell maturation and brain development. We report spontaneous, ultraslow, asynchronous fluctuations in the intracellular Na concentration of neurons and astrocytes. We show that this activity is not correlated with the previously reported synchronous neuronal population bursting or Ca oscillations, both of which occur at much faster timescales. Furthermore, extracellular K concentration remains nearly constant. The spontaneous Na fluctuations disappear after the first postnatal week.
Topics: Action Potentials; Animals; Female; GABA Antagonists; GABAergic Neurons; Interneurons; Male; Mice; Mice, Inbred BALB C; Models, Neurological; Prosencephalon; Pyramidal Cells; Sodium; Sodium Channel Blockers; Sodium Channels
PubMed: 33236936
DOI: 10.1152/jn.00373.2020 -
Journal of Neurophysiology Oct 2021The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a...
The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells-an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons-during simulated θ rhythms. We use previously developed multicompartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs during in vitro and in vivo scenarios contribute to θ. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via postinhibitory rebound mechanisms, and contribute to θ frequency spike resonance during simulated in vivo scenarios. To elicit recruitment similar to in vitro experiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Using in vivo virtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at θ frequencies. Furthermore, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways. How information is processed across different brain structures is an important question that relates to the different functions that the brain performs. Using modeling and theoretical analyses, we show that an inhibitory cell type that only inhibits other inhibitory cells can broaden the window for disinhibition of excitatory cells, manage input pathway switching, and modulate inhibitory cell spiking. This work contributes to the knowledge of how coordination between sensory and memory consolidation information can be attained.
Topics: Animals; CA1 Region, Hippocampal; Computer Simulation; Interneurons; Models, Biological; Nerve Net; Pyramidal Cells; Theta Rhythm
PubMed: 34379493
DOI: 10.1152/jn.00204.2021 -
ELife Oct 2022We interrogated prefrontal circuit function in mice lacking (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed...
We interrogated prefrontal circuit function in mice lacking (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations defined as coactivations within 25 ms were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data, thus, reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting INT responsiveness to glutamatergic drive.
Topics: Animals; Communication; Interneurons; Mice; Nerve Tissue Proteins; Parvalbumins; Prefrontal Cortex; Pyramidal Cells; Schizophrenia
PubMed: 36239988
DOI: 10.7554/eLife.79471 -
The Journal of Neuroscience : the... Feb 2022Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca spike at the apical tuft of pyramidal...
Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca spike at the apical tuft of pyramidal neurons. Characterized by a plateau potential sustained for tens of milliseconds, the Ca spike amplifies excitatory input, facilitates somatic action potentials (APs), and promotes synaptic plasticity. Despite its essential role, the mechanisms regulating it are largely unknown. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the plateau and termination phases of the Ca spike under input current perturbations, long-step current-injections, and variations in the dendritic high-voltage-activated Ca conductance (that occur during cholinergic modulation). We found that, surprisingly, timed excitatory input can shorten the Ca spike duration while inhibitory input can either elongate or terminate it. A significant elongation also occurs when the high-voltage-activated Ca channels (Ca) conductance is increased. To mechanistically understand these phenomena, we analyzed the currents involved in the spike. The plateau and termination phases are almost exclusively controlled by the Ca inward current and the I outward K current. We reduced the full model to a single-compartment model that faithfully preserved the responses of the Ca spike to interventions and consisted of two dynamic variables: the membrane potential and the K-channel activation level. A phase-plane analysis of the reduced model provides testable predictions for modulating the Ca spike and reveals various dynamical regimes that explain the robust nature of the spike. Regulating the duration of the Ca spike significantly impacts the cell synaptic-plasticity window and, as we show, its input-output relationship. Pyramidal neurons are the cortex's principal projection neurons. In their apical tuft, dendritic Ca spikes significantly impact information processing, synaptic plasticity, and the cell's input-output relationship. Therefore, it is essential to understand the mechanisms regulating them. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the Ca spike responses to synaptic perturbations and cholinergic modulation. We showed a counterintuitive phenomenon: early excitatory input shortens the spike, whereas weak inhibition elongates it. Also, we demonstrated that acetylcholine (ACh) extends the spike. Through a reduced model containing only the membrane potential and the K-channel activation level, we explained these phenomena using a phase-plane analysis. Our work provides new information about the robustness of the Ca spike and its controlling mechanisms.
Topics: Acetylcholine; Action Potentials; Animals; Calcium; Dendrites; Humans; Models, Neurological; Neuronal Plasticity; Pyramidal Cells; Synapses
PubMed: 34893549
DOI: 10.1523/JNEUROSCI.1470-21.2021