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Cerebral Cortex (New York, N.Y. : 1991) May 2022The laminar cellular and circuit mechanisms by which the anterior cingulate cortex (ACC) exerts flexible control of motor and affective information for goal-directed...
The laminar cellular and circuit mechanisms by which the anterior cingulate cortex (ACC) exerts flexible control of motor and affective information for goal-directed behavior have not been elucidated. Using multimodal tract-tracing, in vitro patch-clamp recording and computational approaches in rhesus monkeys (M. mulatta), we provide evidence that specialized motor and affective network dynamics can be conferred by layer-specific biophysical and structural properties of ACC pyramidal neurons targeting two key downstream structures -the dorsal premotor cortex (PMd) and the amygdala (AMY). AMY-targeting neurons exhibited significant laminar differences, with L5 more excitable (higher input resistance and action potential firing rates) than L3 neurons. Between-pathway differences were found within L5, with AMY-targeting neurons exhibiting greater excitability, apical dendritic complexity, spine densities, and diversity of inhibitory inputs than PMd-targeting neurons. Simulations using a pyramidal-interneuron network model predict that these layer- and pathway-specific single-cell differences contribute to distinct network oscillatory dynamics. L5 AMY-targeting networks are more tuned to slow oscillations well-suited for affective and contextual processing timescales, while PMd-targeting networks showed strong beta/gamma synchrony implicated in rapid sensorimotor processing. These findings are fundamental to our broad understanding of how layer-specific cellular and circuit properties can drive diverse laminar activity found in flexible behavior.
Topics: Action Potentials; Dendrites; Gyrus Cinguli; Prefrontal Cortex; Pyramidal Cells
PubMed: 34613380
DOI: 10.1093/cercor/bhab347 -
Journal of Neurophysiology Apr 2019Exceeding a certain stimulation strength can prevent the generation of somatic action potentials, as has been demonstrated in vitro with extracellularly stimulated...
Exceeding a certain stimulation strength can prevent the generation of somatic action potentials, as has been demonstrated in vitro with extracellularly stimulated dorsal root ganglion cells as well as retinal ganglion cells. This phenomenon, termed upper threshold, is currently thought to be a consequence of sodium current reversal in strongly depolarized regions. Here we analyze the contribution of membrane kinetics, using spherical model neurons that are stimulated externally with a microelectrode, in more detail. During extracellular pulse application, the electric field depolarizes one part and hyperpolarizes the other part of the cell. Strong transmembrane currents are generated only in the active depolarized region, changing the overall polarization level. The asymmetric membrane voltage distribution caused by the stimulus strongly influences the cell's behavior during and even after the stimulus. Effects on membrane voltage and transmembrane currents during and after the stimulus are shown and discussed in detail. Aside from the sodium current reversal, two more key mechanisms were identified in causing the upper threshold: strong potassium currents and inactivation of sodium channels. The contributions of the mechanisms involved strongly depend on cell properties, stimulus parameters, and other factors such as temperature. The conclusions presented here are based on several retinal ganglion cell models of the Fohlmeister group, a model with original Hodgkin-Huxley membrane, and a pyramidal cell model. NEW & NOTEWORTHY The upper threshold phenomenon in extracellular stimulation is analyzed in detail for spherical cells. Three main mechanisms were identified that prevent the generation of action potentials at high stimulation strengths: 1) strong potassium currents, 2) inactivating sodium ion channels, and 3) sodium current reversal. Ion channel kinetics in retinal ganglion cells, pyramidal cells, and the original Hodgkin-Huxley model were investigated under the influence of an extracellular stimulus.
Topics: Action Potentials; Animals; Models, Neurological; Potassium; Pyramidal Cells; Retinal Ganglion Cells; Sodium
PubMed: 30726157
DOI: 10.1152/jn.00700.2018 -
The Journal of Neuroscience : the... Nov 2015The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K(+) current in many...
UNLABELLED
The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K(+) current in many mammalian central neurons. Kv2.1 exhibits robust expression across many neuron types and is unique in its conditional role in modulating intrinsic excitability through changes in its phosphorylation state, which affect Kv2.1 expression, localization, and function. Much less is known of the highly related Kv2.2 subunit, especially in forebrain neurons. Here, through combined use of cortical layer markers and transgenic mouse lines, we show that Kv2.1 and Kv2.2 are localized to functionally distinct cortical cell types. Kv2.1 expression is consistently high throughout all cortical layers, especially in layer (L) 5b pyramidal neurons, whereas Kv2.2 expression is primarily limited to neurons in L2 and L5a. In addition, L4 of primary somatosensory cortex is strikingly devoid of Kv2.2 immunolabeling. The restricted pattern of Kv2.2 expression persists in Kv2.1-KO mice, suggesting distinct cell- and layer-specific functions for these two highly related Kv2 subunits. Analyses of endogenous Kv2.2 in cortical neurons in situ and recombinant Kv2.2 expressed in heterologous cells reveal that Kv2.2 is largely refractory to stimuli that trigger robust, phosphorylation-dependent changes in Kv2.1 clustering and function. Immunocytochemistry and voltage-clamp recordings from outside-out macropatches reveal distinct cellular expression patterns for Kv2.1 and Kv2.2 in intratelencephalic and pyramidal tract neurons of L5, indicating circuit-specific requirements for these Kv2 paralogs. Together, these results support distinct roles for these two Kv2 channel family members in mammalian cortex.
SIGNIFICANCE STATEMENT
Neurons within the neocortex are arranged in a laminar architecture and contribute to the input, processing, and/or output of sensory and motor signals in a cell- and layer-specific manner. Neurons of different cortical layers express diverse populations of ion channels and possess distinct intrinsic membrane properties. Here, we show that the Kv2 family members Kv2.1 and Kv2.2 are expressed in distinct cortical layers and pyramidal cell types associated with specific corticostriatal pathways. We find that Kv2.1 and Kv2.2 exhibit distinct responses to acute phosphorylation-dependent regulation in brain neurons in situ and in heterologous cells in vitro. These results identify a molecular mechanism that contributes to heterogeneity in cortical neuron ion channel function and regulation.
Topics: Animals; Cells, Cultured; Gene Expression Regulation; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Neocortex; Neurons; Organ Culture Techniques; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Shab Potassium Channels
PubMed: 26538660
DOI: 10.1523/JNEUROSCI.1897-15.2015 -
Molecular Medicine Reports Dec 2018Berberine presents therapeutic ability for various central nervous system disorders, including Alzheimer's disease and cerebral ischemia. The present study investigated...
Berberine presents therapeutic ability for various central nervous system disorders, including Alzheimer's disease and cerebral ischemia. The present study investigated the role of berberine in nerve regeneration and analyzed the potential mechanism mediated by berberine in hippocampal pyramidal neurons. Reverse transcription‑quantitative poylmerase chain reaction, western blot, TUNEL assay and immunofluorescence were used to analyze the therapeutic effects of berberine on nerve regeneration. Berberine treatment increased growth and viability of hippocampal pyramidal neurons. Berberine treatment inhibited apoptosis of hippocampal pyramidal neurons and increased apoptosis regulator Bcl‑2 and Bcl‑w expression. Neuroinflammation of tumor necrosis factor α, interleukin (IL)1β, IL6 levels and autophagy‑related proteins microtubule‑associated proteins 1A/1B light chain 3B, autophagy related 16 like 1 and autophagy related 7 were downregulated by berberine treatment in hippocampal pyramidal neurons. Notably, study has found that berberine increased insulin-like growth factor receptor (IGFR) and decreased c‑Jun N‑terminal kinase (JNK) and protein kinase B (AKT) expression in hippocampal pyramidal neurons. IGFR antagonist abolished berberine‑increased growth of hippocampal pyramidal neurons. In conclusion, these results indicate that berberine can promote nerve regeneration through IGFR‑mediated JNK‑AKT signal pathway.
Topics: Animals; Apoptosis; Berberine; Cell Line; Cell Survival; MAP Kinase Kinase 4; Male; Mice; Nerve Regeneration; Proto-Oncogene Proteins c-akt; Pyramidal Cells; Receptors, Somatomedin; Signal Transduction
PubMed: 30272344
DOI: 10.3892/mmr.2018.9508 -
Frontiers in Neural Circuits 2016Inhibitory circuitry plays an integral role in cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has...
Inhibitory circuitry plays an integral role in cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST) interneurons onto pyramidal cells (PCs), parvalbumin (PV) interneurons, and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre, and G42) that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS) interneurons rather than regular (RS) or low threshold spiking (LTS) phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that SST interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing.
Topics: Animals; Cerebral Cortex; Female; Interneurons; Male; Mice; Mice, Transgenic; Neocortex; Neural Inhibition; Optogenetics; Parvalbumins; Piriform Cortex; Pyramidal Cells; Somatostatin
PubMed: 27582691
DOI: 10.3389/fncir.2016.00062 -
Journal of Neurophysiology Jun 2019The cortex contains multiple neuron types with specific connectivity and functions. Recent progress has provided a better understanding of the interactions of these... (Review)
Review
The cortex contains multiple neuron types with specific connectivity and functions. Recent progress has provided a better understanding of the interactions of these neuron types as well as their output organization particularly for the frontal cortex, with implications for the circuit mechanisms underlying cortical oscillations that have cognitive functions. Layer 5 pyramidal cells (PCs) in the frontal cortex comprise two major subtypes: crossed-corticostriatal (CCS) and corticopontine (CPn) cells. Functionally, CCS and CPn cells exhibit similar phase-dependent firing during gamma waves but participate in two distinct subnetworks that are linked unidirectionally from CCS to CPn cells. GABAergic parvalbumin-expressing fast-spiking (PV-FS) cells, necessary for gamma oscillation, innervate PCs, with stronger and global inhibition to somata and weaker and localized inhibitions to dendritic shafts/spines. While PV-FS cells form reciprocal connections with both CCS and CPn cells, the excitation from CPn to PV-FS cells exhibits short-term synaptic dynamics conducive for oscillation induction. The electrical coupling between PV-FS cells facilitates spike synchronization among PV-FS cells receiving common excitatory inputs from local PCs and inhibits other PV-FS cells via electrically communicated spike afterhyperpolarizations. These connectivity characteristics can promote synchronous firing in the local networks of CPn cells and firing of some CCS cells by anode-break excitation. Thus subsets of L5 CCS and CPn cells within different levels of connection hierarchy exhibit coordinated activity via their common connections with PV-FS cells, and the resulting PC output drives diverse neuronal targets in cortical layer 1 and the striatum with specific temporal precision, expanding the computational power of the cortical network.
Topics: Animals; Brain Waves; Corpus Striatum; Frontal Lobe; GABAergic Neurons; Nerve Net; Parvalbumins; Pyramidal Cells; Rats
PubMed: 30995139
DOI: 10.1152/jn.00778.2018 -
Neuron Nov 2023Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABARs)....
Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABARs). Despite their fundamental role, it is still not known how GABARs signal in the intact brain. Here, we use in vivo gramicidin recordings to investigate synaptic GABAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anesthetized cortex, synaptic GABARs exert classic hyperpolarizing effects. In contrast, GABAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAR equilibrium potentials (E), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. Synaptic E observed in awake cortex facilitates the desynchronizing effects of inhibitory inputs upon local networks, which increases the flexibility of spiking responses to external inputs. Our findings therefore suggest that GABAR signaling adapts to optimize cortical functions.
Topics: Mice; Animals; Receptors, GABA-A; Chlorides; Neurons; Pyramidal Cells; gamma-Aminobutyric Acid; Mammals
PubMed: 37659408
DOI: 10.1016/j.neuron.2023.08.005 -
Nature Communications Dec 2023The prefrontal cortex maintains information in memory through static or dynamic population codes depending on task demands, but whether the population coding schemes...
The prefrontal cortex maintains information in memory through static or dynamic population codes depending on task demands, but whether the population coding schemes used are learning-dependent and differ between cell types is currently unknown. We investigate the population coding properties and temporal stability of neurons recorded from male macaques in two mapping tasks during and after stimulus-response associative learning, and then we use a Strategy task with the same stimuli and responses as control. We identify a heterogeneous population coding for stimuli, responses, and novel associations: static for putative pyramidal cells and dynamic for putative interneurons that show the strongest selectivity for all the variables. The population coding of learned associations shows overall the highest stability driven by cell types, with interneurons changing from dynamic to static coding after successful learning. The results support that prefrontal microcircuitry expresses mixed population coding governed by cell types and changes its stability during associative learning.
Topics: Animals; Male; Prefrontal Cortex; Neurons; Learning; Pyramidal Cells; Interneurons; Macaca
PubMed: 38097560
DOI: 10.1038/s41467-023-43712-2 -
ACS Chemical Neuroscience Apr 2018Pyramidal cells and astrocytes have differential susceptibility to oxygen-glucose deprivation and reperfusion (OGD-RP). It is known that excessive reactive oxygen...
Pyramidal cells and astrocytes have differential susceptibility to oxygen-glucose deprivation and reperfusion (OGD-RP). It is known that excessive reactive oxygen species (ROS) in mitochondria initiates cell death, while glutathione (GSH) is one of the major defenses against ROS. Although it is known that astrocytes contain a higher concentration of GSH than neurons, and that astrocytes can provide neurons with GSH, we are unaware of a detailed and quantitative examination of the dynamic changes in the mitochondrial GSH system in the two cell types during OGD-RP. Here, we determined mitochondrial membrane potential and the degrees of oxidation of the mitochondrially targeted roGFP-based sensors for hydrogen peroxide (OxD) and GSH (OxD). We also developed a method to estimate the mitochondrial GSH (mGSH) concentration in single cells in the CA1 region of organotypic hippocampal slice cultures at several time-points during OGD-RP. We find that mitochondrial membrane potential drops in pyramidal cells during OGD while it is relatively stable in astrocytes. In both types of cell, the mitochondrial membrane potential decreases during RP. During OGD-RP, mitochondrial peroxide levels are the same. Astrocytic mGSH is more than four times higher than pyramidal cell mGSH (3.2 vs 0.7 mM). Astrocytic mGSH is drained from mitochondria during OGD, whereas in pyramidal cells it remains fairly constant. OxD prior to and during OGD is lower (less oxidized) in pyramidal cells than in astrocytes, but the two nearly converge during RP. The larger changes of redox status in the GSH system in pyramidal cells than astrocytes is an upstream sign of the higher mortality of the pyramidal cells after facing an insult. The pattern of [mGSH] changes in the two cell types could be recognized as another mechanism by which astrocytes protect neurons from transient, extreme conditions.
Topics: Animals; Astrocytes; Cells, Cultured; Glucose; Hippocampus; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Oxygen; Pyramidal Cells; Reactive Oxygen Species
PubMed: 29172440
DOI: 10.1021/acschemneuro.7b00369 -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2024The high-order cognitive and executive functions are necessary for an individual to survive. The densely bidirectional innervations between the medial prefrontal cortex...
The high-order cognitive and executive functions are necessary for an individual to survive. The densely bidirectional innervations between the medial prefrontal cortex (mPFC) and the mediodorsal thalamus (MD) play a vital role in regulating high-order functions. Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysiological properties, but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood. The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD. In the past, the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions. But, it is a low efficient method for characterizing the circuit-specific neurons. The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method, to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons, and to achieve more accurate and efficient identification of the properties from a small size sample of neurons. We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions. The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology. MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC. The morphological characteristics of the two subtypes (ET-1 and ET-2) of mPFC pyramidal neurons innervated by MD are different, with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons. These results suggest that the electrophysiological properties of MD- innervated pyramidal neurons within mPFC correlate with their morphological properties, indicating that the different roles of these two subclasses in local circuits within PFC, as well as in PFC-cortical/subcortical brain region circuits.
Topics: Pyramidal Cells; Prefrontal Cortex; Animals; Rats; Mediodorsal Thalamic Nucleus; Male; Electrophysiological Phenomena; Neural Pathways; Machine Learning; Rats, Sprague-Dawley; Patch-Clamp Techniques
PubMed: 38658373
DOI: No ID Found