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Rhythmic activity is ubiquitous in neural systems, with theta-resonant pyramidal neurons integrating rhythmic inputs in many cortical structures. Impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs, but it assumes that the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms (voltage-gated ion channels). The goals of this work were to 1 ) develop an analysis method to evaluate membrane responses in this nonlinear domain and 2 ) explore phase relationships between rhythmic stimuli and subthreshold and spiking membrane potential (V memb ) responses in models of theta-resonant pyramidal neurons. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold theta-rhythmic stimuli produced nonstationary V memb responses. Sinusoidal inputs produced "phase retreat": action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Sinusoidal current with increasing amplitude over cycles produced "phase advance": action potentials occurred progressively earlier. Phase retreat, phase advance, and subthreshold phase shifts were modulated by multiple ion channel conductances. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, also observed in hippocampal CA1 neurons. NEW & NOTEWORTHY We augmented electrical impedance analysis to characterize phase shifts between large-amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation vs. inhibition, as well as shifts in spike timing over multiple input cycles, in theta-resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena such as phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.

BACE1 is the rate-limiting enzyme for β-amyloid (Aβ) production and therefore is considered a prime drug target for treating Alzheimer's disease (AD). Nevertheless, the BACE1 inhibitors failed in clinical trials, even exhibiting cognitive worsening, implying that BACE1 may function in regulating cognition-relevant neural circuits. Here, we found that parvalbumin-positive inhibitory interneurons (PV INs) in hippocampal CA1 express BACE1 at a high level. We designed and developed a mouse strain with conditional knockout of BACE1 in PV neurons. The CA1 fast-spiking PV INs with BACE1 deletion exhibited an enhanced response of postsynaptic N-methyl-D-aspartate (NMDA) receptors to local stimulation on CA1 oriens, with average intrinsic electrical properties and fidelity in synaptic integration. Intriguingly, the BACE1 deletion reorganized the CA1 recurrent inhibitory motif assembled by the heterogeneous pyramidal neurons (PNs) and the adjacent fast-spiking PV INs from the superficial to the deep layer. Moreover, the conditional BACE1 deletion impaired the AMPARs-mediated excitatory transmission of deep CA1 PNs. Further rescue experiments confirmed that these phenotypes require the enzymatic activity of BACE1. Above all, the BACE1 deletion resets the priming of the fear memory extinction. Our findings suggest a neuron-specific working model of BACE1 in regulating learning and memory circuits. The study may provide a potential path of targeting BACE1 and NMDAR together to circumvent cognitive worsening due to a single application of BACE1 inhibitor in AD patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Excitatory spiny stellate neurons are prominently featured in the cortical circuits of sensory modalities that provide high salience and high acuity representations of the environment. These specialized neurons are considered developmentally linked to bottom-up inputs from the thalamus, however, the molecular mechanisms underlying their diversification and function are unknown. Here, we investigated this in mouse somatosensory cortex, where spiny stellate neurons and pyramidal neurons have distinct roles in processing whisker-evoked signals. Utilizing spatial transcriptomics, we identified reciprocal patterns of gene expression which correlated with these cell-types and were linked to innervation by specific thalamic inputs during development. Genetic manipulation that prevents the acquisition of spiny stellate fate highlighted an important role for these neurons in processing distinct whisker signals within functional cortical columns, and as a key driver in the formation of specific whisker-related circuits in the cortex., (© 2023. The Author(s).)

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Fear-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterize mouse phenotypes that spontaneously show fear-independent behavioral traits predicting adaptive or maladaptive fear extinction. We find that, already before fear conditioning, specific morphological, electrophysiological, and transcriptomic patterns of cortical and amygdala pyramidal neurons predispose to fear-related disorders. Finally, by using an optogenetic approach, we show the possibility to rescue inefficient fear extinction by activating infralimbic pyramidal neurons and to impair fear extinction by activating prelimbic pyramidal neurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cortical circuit function is regulated by extensively interconnected, diverse populations of GABAergic interneurons that may play key roles in shaping circuit operation according to behavioral context. A specialized population of interneurons that co-express vasoactive intestinal peptides (VIP-INs) are activated during arousal and innervate other INs and pyramidal neurons (PNs). Although state-dependent modulation of VIP-INs has been extensively studied, their role in regulating sensory processing is less well understood. We examined the impact of VIP-INs in the primary visual cortex of awake behaving mice. Loss of VIP-IN activity alters the behavioral state-dependent modulation of somatostatin-expressing INs (SST-INs) but not PNs. In contrast, reduced VIP-IN activity globally disrupts visual feature selectivity for stimulus size. Moreover, the impact of VIP-INs on perceptual behavior varies with context and is more acute for small than large visual cues. VIP-INs thus contribute to both state-dependent modulation of cortical activity and sensory context-dependent perceptual performance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hippocampal sharp-wave ripples (SPW-Rs) are critical for memory consolidation and retrieval. The neuronal content of spiking during SPW-Rs is believed to be under the influence of neocortical inputs via the entorhinal cortex (EC). Optogenetic silencing of the medial EC (mEC) reduced the incidence of SPW-Rs with minor impacts on their magnitude or duration, similar to local CA1 silencing. The effect of mEC silencing on CA1 firing and field potentials was comparable to the effect of transient cortex-wide DOWN states of non-REM (NREM) sleep, implying that decreased SPW-R incidence in both cases is due to tonic disfacilitation of hippocampal circuits. The neuronal composition of CA1 pyramidal neurons during SPW-Rs was altered by mEC silencing but was restored immediately after silencing. We suggest that the mEC provides both tonic and transient influences on hippocampal network states by timing the occurrence of SPW-Rs and altering their neuronal content., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. Although there is evidence that this diversity is functionally relevant, the circuit implications of this diversity are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes and found that each subtype possesses a unique laminar organization and stereotyped axonal projection pattern. Using these strategies, we examined the afferent and efferent connectivity of three subtypes (two Martinotti and one non-Martinotti) and demonstrated that they possess selective connectivity with intratelecephalic or pyramidal tract neurons. Even when two subtypes targeted the same pyramidal cell type, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin interneurons form cell-type-specific cortical circuits., Competing Interests: Declaration of interests G.F. is a founder of Regel Therapeutics, which has no competing interests with the present manuscript. G.F. is an advisor for Neuron and Annual Review of Neuroscience., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sharp-wave ripples (SWRs) are transient high-frequency oscillations of local field potentials (LFPs) in the hippocampus and play a critical role in memory consolidation. During SWRs, CA1 pyramidal cells exhibit rapid spike sequences that often replay the sequential activity that occurred during behavior. This temporally organized firing activity gradually emerges during 2 weeks after the eye opening; however, it remains unclear how the organized spikes during SWRs mature at the intracellular membrane potential ( V m) level. Here, we recorded V m of CA1 pyramidal cells simultaneously with hippocampal LFPs from anesthetized immature mice of either sex after the developmental emergence of SWRs. On postnatal days 16 and 17, V m dynamics around SWRs were premature, characterized by prolonged depolarizations without either pre- or post-SWR hyperpolarizations. The biphasic hyperpolarizations, features typical of adult SWR-relevant V m, formed by approximately postnatal day 30. This V m maturation was associated with an increase in SWR-associated inhibitory inputs to pyramidal cells. Thus, the development of SWR-relevant inhibition restricts the temporal windows for spikes of pyramidal cells and allows CA1 pyramidal cells to organize their spike sequences during SWRs. SIGNIFICANCE STATEMENT Sharp-wave ripples (SWRs) are prominent hippocampal oscillations and play a critical role in memory consolidation. During SWRs, hippocampal neurons synchronously emit spikes with organized temporal patterns. This temporal structure of spikes during SWRs develops during the third and fourth postnatal weeks, but the underlying mechanisms are not well understood. Here, we recorded in vivo membrane potentials from hippocampal neurons in premature mice and suggest that the maturation of SWR-associated inhibition enables hippocampal neurons to produce precisely controlled spike times during SWRs., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 the authors.)

Discerning the contribution of specific ionic currents to complex neuronal dynamics is a difficult, but important, task. This challenge is exacerbated in the human setting, although the widely characterized uniqueness of the human brain compared with preclinical models necessitates the direct study of human neurons. Neuronal spiking frequency preference is of particular interest given its role in rhythm generation and signal transmission in cortical circuits. Here, we combine the frequency-dependent gain (FDG), a measure of spiking frequency preference, and novel in silico analyses to dissect the contributions of individual ionic currents to the suprathreshold features of human layer 5 (L5) neurons captured by the FDG. We confirm that a contemporary model of such a neuron, primarily constrained to capture subthreshold activity driven by the hyperpolarization-activated cyclic nucleotide gated (h-) current, replicates key features of the in vitro FDG both with and without h-current activity. With the model confirmed as a viable approximation of the biophysical features of interest, we applied new analysis techniques to quantify the activity of each modeled ionic current in the moments before spiking, revealing unique dynamics of the h-current. These findings motivated patch-clamp recordings in analogous rodent neurons to characterize their FDG, which confirmed that a biophysically detailed model of these neurons captures key interspecies differences in the FDG. These differences are correlated with distinct contributions of the h-current to neuronal activity. Together, this interdisciplinary and multispecies study provides new insights directly relating the dynamics of the h-current to suprathreshold spiking frequency preference in human L5 neurons., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Inibhunu et al.)

Regional brain activity often decreases from baseline levels in response to external events, but how neurons develop such negative responses is unclear. To study this, we leveraged the negative response that develops in the primary motor cortex (M1) after classical fear learning. We trained mice with a fear conditioning paradigm while imaging their brains with standard two-photon microscopy. This enabled monitoring changes in neuronal responses to the tone with synaptic resolution through learning. We found that M1 layer 5 pyramidal neurons (L5 PNs) developed negative tone responses within an hour after conditioning, which depended on the weakening of their dendritic spines that were active during training. Blocking this form of anti-Hebbian plasticity using an optogenetic manipulation of CaMKII activity disrupted negative tone responses and freezing. Therefore, reducing the strength of spines active at the time of memory encoding leads to negative responses of L5 PNs. In turn, these negative responses curb M1's capacity for promoting movement, thereby aiding freezing. Collectively, this work provides a mechanistic understanding of how area-specific negative responses to behaviorally relevant cues can be achieved., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In schizophrenia, layer 3 pyramidal neurons (L3PNs) of the dorsolateral prefrontal cortex exhibit deficits in markers of excitatory synaptic inputs that are thought to disrupt the patterns of neural network activity essential for cognitive function. These deficits are usually interpreted under Irwin Feinberg's hypothesis of altered synaptic pruning, which postulates that normal periadolescent pruning, thought to preferentially eliminate weak/immature synapses, is altered in schizophrenia. However, it remains unknown whether periadolescent pruning on L3PNs in the primate dorsolateral prefrontal cortex selectively eliminates weak excitatory synapses or uniformly eliminates excitatory synapses across the full distribution of synaptic strengths., Methods: To distinguish between these alternative models of synaptic pruning, we assessed the densities of dendritic spines, the site of most excitatory inputs to L3PNs, and the distributions of excitatory synaptic strengths in dorsolateral prefrontal cortex L3PNs from male and female monkeys across the periadolescent period of synaptic pruning. We used patch-clamp methods in acute brain slices to record miniature excitatory synaptic currents and intracellular filling with biocytin to quantify dendritic spines., Results: On L3PNs, dendritic spines exhibited the expected age-related decline in density, but mean synaptic strength and the shape of synaptic strength distributions remained stable with age., Conclusions: The absence of age-related differences in mean synaptic strength and synaptic strength distributions supports the model of a uniform pattern of synaptic pruning across the full range of synaptic strengths. The implications of these findings for the pathogenesis and functional consequences of dendritic spine deficits in schizophrenia are discussed., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Hippocampal pyramidal cells represent an animal's position in space together with specific contexts and events. However, it is largely unknown how distinct types of GABAergic interneurons contribute to such computations. We recorded from the intermediate CA1 hippocampus of head-fixed mice exhibiting odor-to-place memory associations during navigation in a virtual reality (VR). The presence of an odor cue and its prediction of a different reward location induced a remapping of place cell activity in the virtual maze. Based on this, we performed extracellular recording and juxtacellular labeling of identified interneurons during task performance. The activity of parvalbumin (PV)-expressing basket, but not of PV-expressing bistratified cells, reflected the expected contextual change in the working-memory-related sections of the maze. Some interneurons, including identified cholecystokinin-expressing cells, decreased activity during visuospatial navigation and increased activity during reward. Our findings suggest that distinct types of GABAergic interneuron are differentially involved in cognitive processes of the hippocampus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus., (© 2023 Wiley Periodicals LLC.)

Complex spike bursting (CSB) is a characteristic electrophysiological signature exhibited by several neuronal subtypes and has been implicated in neural plasticity, learning, perception, anaesthesia and active sensing. Here, we address how pronounced intrinsic and synaptic heterogeneities affect CSB, with hippocampal CA3 pyramidal neurons (CA3PNs), where CSB emergence and heterogeneities are well characterized, as a substrate. We randomly generated 12,000 unique models and found 236 valid models that satisfied 11 characteristic CA3PN measurements. These morphologically and biophysically realistic valid models accounted for gating kinetics and somatodendritic expression profiles of 10 active ion channels. This heterogeneous population of valid models was endowed with broad distributions of underlying parameters showing weak pairwise correlations. We found two functional subclasses of valid models, intrinsically bursting and regular spiking, with significant differences in the expression of calcium and calcium-activated potassium conductances. We triggered CSB in all 236 models through different intrinsic or synaptic protocols and observed considerable heterogeneity in CSB propensity and properties spanning models and protocols. Finally, we used virtual knockout analyses and showed that synergistic interactions between intrinsic and synaptic mechanisms regulated CSB emergence and dynamics. Specifically, although there was a dominance of calcium and calcium-activated potassium channels in the emergence of CSB, individual deletion of none of the several ion channels or N-methyl-d-aspartate receptors resulted in the complete elimination of CSB across all models. Together, our analyses critically implicate ion-channel degeneracy in the robust emergence of CSB and other characteristic signatures of CA3PNs, despite pronounced heterogeneities in underlying intrinsic and synaptic properties. KEY POINTS: An unbiased stochastic search algorithm yielded a heterogeneous population of morphologically and biophysically realistic CA3 pyramidal neuronal models matching several signature electrophysiological characteristics. Two functional subclasses of valid models were identified with intrinsically bursting (IB) and regular spiking (RS) characteristics, which exhibited differential localization within the parametric space with linear and non-linear dimension reduction analyses. Calcium and calcium-activated potassium channels distinguished IB from RS models, apart from playing dominant roles in the emergence of complex spike bursting (CSB). The impact of deleting individual ion channels or N-methyl-d-aspartate receptors was variable across different models and differential for each channel/receptor, pointing to ion-channel degeneracy in the emergence of CSB. Biological heterogeneities across different neurons of the same subtype, ion-channel degeneracy and state-dependent changes (involving activity-dependent plasticity, pathology, and neuromodulation of intrinsic and synaptic properties) need to be considered carefully in assessing the propensity and dynamics of CSB in different neuronal subtypes., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Neuron models with explicit dendritic dynamics have shed light on mechanisms for coincidence detection, pathway selection and temporal filtering. However, it is still unclear which morphological and physiological features are required to capture these phenomena. In this work, we introduce the Tripod neuron model and propose a minimal structural reduction of the dendritic tree that is able to reproduce these computations. The Tripod is a three-compartment model consisting of two segregated passive dendrites and a somatic compartment modelled as an adaptive, exponential integrate-and-fire neuron. It incorporates dendritic geometry, membrane physiology and receptor dynamics as measured in human pyramidal cells. We characterize the response of the Tripod to glutamatergic and GABAergic inputs and identify parameters that support supra-linear integration, coincidence-detection and pathway-specific gating through shunting inhibition. Following NMDA spikes, the Tripod neuron generates plateau potentials whose duration depends on the dendritic length and the strength of synaptic input. When fitted with distal compartments, the Tripod encodes previous activity into a dendritic depolarized state. This dendritic memory allows the neuron to perform temporal binding, and we show that it solves transition and sequence detection tasks on which a single-compartment model fails. Thus, the Tripod can account for dendritic computations previously explained only with more detailed neuron models or neural networks. Due to its simplicity, the Tripod neuron can be used efficiently in simulations of larger cortical circuits. KEY POINTS: We present a neuron model, called the Tripod, with two segregated dendritic branches that are connected to an axosomatic compartment. Each branch implements inhibitory GABAergic and excitatory glutamatergic synaptic transmission, including voltage-gated NMDA receptors. Dendrites are modelled on relevant geometric and physiological parameters measured in human pyramidal cells. The neuron reproduces classical dendritic computations, such as coincidence detection and pathway selection via shunting inhibition, that are beyond the scope of point-neuron models. Under some conditions, dendritic NMDA spikes cause plateau potentials, and we show that they provide a form of short-term memory which is useful for sequence recognition. The dendritic structure of the Tripod neuron is sufficiently simple to be integrated into efficient network simulations and studied in a broad functional context., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background and Aim: Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs) serve a crucial role in regulating dendritic spine formation and plasticity. However, the mechanisms that are involved are poorly understood. This study is designed to understand whether the upregulation of acetylated α-tubulin (α-Ac-Tub, a marker for stable, and polymerized MTs) could alleviate injury to the dendritic spines in the penumbra area and motor dysfunction after ischemic stroke., Methods: Ischemic stroke was mimicked both in an in vivo and in vitro setup using middle cerebral artery occlusion and oxygen-glucose deprivation models. Thy1-YFP mice were utilized to observe the morphology of the dendritic spines in the penumbra area. MEC17 is the specific acetyltransferase of α-tubulin. Thy1 Cre ERT2-eYFP and MEC17 fl/fl mice were mated to produce mice with decreased expression of α-Ac-Tub in dendritic spines of pyramidal neurons in the cerebral cortex. Moreover, AAV-PHP.B-DIO-MEC17 virus and tubastatin A (TBA) were injected into Thy1 Cre ERT2-eYFP and Thy1-YFP mice to increase α-Ac-Tub expression. Single-pellet retrieval, irregular ladder walking, rotarod, and cylinder tests were performed to test the motor function after the ischemic stroke., Results: α-Ac-Tub was colocalized with postsynaptic density 95. Although knockout of MEC17 in the pyramidal neurons did not affect the density of the dendritic spines, it significantly aggravated the injury to them in the penumbra area and motor dysfunction after stroke. However, MEC17 upregulation in the pyramidal neurons and TBA treatment could maintain mature dendritic spine density and alleviate motor dysfunction after stroke., Conclusion: Our study demonstrated that α-Ac-Tub plays a crucial role in the maintenance of the structure and functions of mature dendritic spines. Moreover, α-Ac-Tub protected the dendritic spines in the penumbra area and alleviated motor dysfunction after stroke., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We found that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, with tuning refined through suppression of irrelevant neuronal activity. ChCs contribute to learning-dependent refinements by providing selective inhibitory control over individual pyramidal neurons rather than global suppression. Quantitative analysis of structural plasticity across axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a targeted cell-specific manner., (© 2023. The Author(s).)

In excitatory hippocampal pyramidal neurons, integrin β3 is critical for synaptic maturation and plasticity in vitro. Itgb3 is a potential autism susceptibility gene that regulates dendritic morphology in the cerebral cortex in a cell-specific manner. However, it is unknown what role Itgb3 could have in regulating hippocampal pyramidal dendritic morphology in vivo, a key feature that is aberrant in many forms of autism and intellectual disability. We found that Itgb3 mRNA is expressed in the stratum pyramidale of CA3. We examined the apical dendritic morphology of CA3 hippocampal pyramidal neurons in conditional Itgb3 knockouts and controls, utilizing the Thy1-GFP-M line. We fully reconstructed the apical dendrite of each neuron and determined each neuron's precise location along the dorsoventral, proximodistal, and radial axes of the stratum pyramidale. We found a very strong effect for Itgb3 expression on CA3 apical dendritic morphology: neurons from conditional Itgb3 knockouts had longer and thinner apical dendrites than controls, particularly in higher branch orders. We also assessed potential relationships between pairs of topographic or morphological variables, finding that most variable pairs were free from any linear relationships to each other. We also found that some neurons from controls, but not conditional Itgb3 knockouts, had a graded pattern of overall diameter along the dorsoventral and proximodistal axes of the stratum pyramidale of CA3. Taken together, Itgb3 is essential for constructing normal dendritic morphology in pyramidal neurons throughout CA3., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Neuronal hyperexcitability is a pathological characteristic of Alzheimer's disease (AD). Three main mechanisms have been proposed to explain it: (i) dendritic degeneration leading to increased input resistance, (ii) ion channel changes leading to enhanced intrinsic excitability, and (iii) synaptic changes leading to excitation-inhibition (E/I) imbalance. However, the relative contribution of these mechanisms is not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling of neuronal excitability in reconstructed CA1 pyramidal neurons from wild-type and APP/PS1 mice, a well-established animal model of AD. We show that, for synaptic activation, the excitability-promoting effects of dendritic degeneration are cancelled out by decreased excitation due to synaptic loss. We find an interesting balance between excitability regulation and an enhanced degeneration in the basal dendrites of APP/PS1 cells, potentially leading to increased excitation by the apical but decreased excitation by the basal Schaffer collateral pathway. Furthermore, our simulations reveal three pathomechanistic scenarios that can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APP/PS1 mice: scenario 1: enhanced E/I ratio; scenario 2: alteration of intrinsic ion channels (I AHP down-regulated; I Nap , I Na and I CaT up-regulated) in addition to enhanced E/I ratio; and scenario 3: increased excitatory burst input. Our work supports the hypothesis that pathological network and ion channel changes are major contributors to neuronal hyperexcitability in AD. Overall, our results are in line with the concept of multi-causality according to which multiple different disruptions are separately sufficient but no single particular disruption is necessary for neuronal hyperexcitability. KEY POINTS: This work presents simulations of synaptically driven responses in pyramidal cells (PCs) with Alzheimer's disease (AD)-related dendritic degeneration. Dendritic degeneration alone alters PC responses to layer-specific input but additional pathomechanistic scenarios are required to explain neuronal hyperexcitability in AD as follows. Possible scenario 1: AD-related increased excitatory input together with decreased inhibitory input (E/I imbalance) can lead to hyperexcitability in PCs. Possible scenario 2: changes in E/I balance combined with altered ion channel properties can account for hyperexcitability in AD. Possible scenario 3: burst hyperactivity of the surrounding network can explain hyperexcitability of PCs during AD., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Activity-dependent changes in membrane excitability are observed in neurons across brain areas and represent a cell-autonomous form of plasticity (intrinsic plasticity; IP) that in itself does not involve alterations in synaptic strength (synaptic plasticity; SP). Non-homeostatic IP may play an essential role in learning, e.g. by changing the action potential threshold near the soma. A computational problem, however, arises from the implication that such amplification does not discriminate between synaptic inputs and therefore may reduce the resolution of input representation. Here, we investigate consequences of IP for the performance of an artificial neural network in (a) the discrimination of unknown input patterns and (b) the recognition of known/learned patterns. While negative changes in threshold potentials in the output layer indeed reduce its ability to discriminate patterns, they benefit the recognition of known but incompletely presented patterns. An analysis of thresholds and IP-induced threshold changes in published sets of physiological data obtained from whole-cell patch-clamp recordings from L2/3 pyramidal neurons in (a) the primary visual cortex (V1) of awake macaques and (b) the primary somatosensory cortex (S1) of mice in vitro, respectively, reveals a difference between resting and threshold potentials of ∼15 mV for V1 and ∼25 mV for S1, and a total plasticity range of ∼10 mV (S1). The most efficient activity pattern to lower threshold is paired cholinergic and electric activation. Our findings show that threshold reduction promotes a shift in neural coding strategies from accurate faithful representation to interpretative assignment of input patterns to learned object categories. KEY POINTS: Intrinsic plasticity may change the action potential threshold near the soma of neurons (threshold plasticity), thus altering the input-output function for all synaptic inputs 'upstream' of the plasticity location. A potential problem arising from this shared amplification is that it may reduce the ability to discriminate between different input patterns. Here, we assess the performance of an artificial neural network in the discrimination of unknown input patterns as well as the recognition of known patterns subsequent to changes in the spike threshold. We observe that negative changes in threshold potentials do reduce discrimination performance, but at the same time improve performance in an object recognition task, in particular when patterns are incompletely presented. Analysis of whole-cell patch-clamp recordings from pyramidal neurons in the primary somatosensory cortex (S1) of mice reveals that negative threshold changes preferentially result from electric stimulation of neurons paired with the activation of muscarinic acetylcholine receptors., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Although electrophysiologists have been recording intracellular neural activity routinely ever since the ground-breaking work of Hodgkin and Huxley, and extracellular multichannel electrodes have also been used frequently and extensively, a practical experimental method to track changes in membrane potential along a complete single neuron is still lacking. Instead of obtaining multiple intracellular measurements on the same neuron, we propose an alternative method by combining single-channel somatic patch-clamp and multichannel extracellular potential recordings. In this work, we show that it is possible to reconstruct the complete spatiotemporal distribution of the membrane potential of a single neuron with the spatial resolution of an extracellular probe during action potential generation. Moreover, the reconstruction of the membrane potential allows us to distinguish between the two major but previously hidden components of the current source density (CSD) distribution: the resistive and the capacitive currents. This distinction provides a clue to the clear interpretation of the CSD analysis, because the resistive component corresponds to transmembrane ionic currents (all the synaptic, voltage-sensitive and passive currents), whereas capacitive currents are considered to be the main contributors of counter-currents. We validate our model-based reconstruction approach on simulations and demonstrate its application to experimental data obtained in vitro via paired extracellular and intracellular recordings from a single pyramidal cell of the rat hippocampus. In perspective, the estimation of the spatial distribution of resistive membrane currents makes it possible to distiguish between active and passive sinks and sources of the CSD map and the localization of the synaptic input currents, which make the neuron fire. KEY POINTS: A new computational method is introduced to calculate the unbiased current source density distribution on a single neuron with known morphology. The relationship between extracellular and intracellular electric potential is determined via mathematical formalism, and a new reconstruction method is applied to reveal the full spatiotemporal distribution of the membrane potential and the resistive and capacitive current components. The new reconstruction method was validated on simulations. Simultaneous and colocalized whole-cell patch-clamp and multichannel silicon probe recordings were performed from the same pyramidal neuron in the rat hippocampal CA1 region, in vitro. The method was applied in experimental measurements and returned precise and distinctive characteristics of various intracellular phenomena, such as action potential generation, signal back-propagation and the initial dendritic depolarization preceding the somatic action potential., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Sensory experience regulates the structural and functional wiring of neuronal circuits, during development and throughout adulthood. Here, we review current knowledge of how experience affects structural plasticity of pyramidal neurons in the sensory cortices. We discuss the pros and cons of existing labeling approaches, as well as what structural parameters are most plastic. We further discuss how recent advances in sparse labeling of specific neuronal subtypes, as well as development of techniques that allow fast, high resolution imaging in large fields, would enable future studies to address currently unanswered questions in the field of structural plasticity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Xiang Yu reports a relationship with Ministry of Science and Technology of the People's Republic of China that includes: funding grants. Xiang Yu reports a relationship with National Natural Science Foundation of China that includes: funding grants. Xiang Yu reports a relationship with Special Project for Research and Development in Key Areas of Guangdong Province that includes: funding grants., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex in rats. When these effects of play experience occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the medial prefrontal cortex and the orbitofrontal cortex. We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42), and adult (P85) rats after social play deprivation (between P21 and P42). The development of these prefrontal cortex subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was higher in the orbitofrontal cortex than in the medial prefrontal cortex. Social play deprivation did not affect excitatory currents, but reduced inhibitory transmission in both medial prefrontal cortex and orbitofrontal cortex. Intriguingly, the reduction occurred in the medial prefrontal cortex during social play deprivation, whereas the reduction in the orbitofrontal cortex only became manifested after social play deprivation. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Muscarinic acetylcholine receptors are well-known for their crucial involvement in hippocampus-dependent learning and memory, but the exact roles of the various receptor subtypes (M1-M5) are still not fully understood. Here, we studied how M1 and M3 receptors affect plasticity at the mossy fiber (MF)-CA3 pyramidal cell synapse. In hippocampal slices from M1/M3 receptor double knockout (M1/M3-dKO) mice, the signature short-term plasticity of the MF-CA3 synapse was not significantly affected. However, the rather unique NMDA receptor-independent and presynaptic form of long-term potentiation (LTP) of this synapse was much larger in M1/M3-deficient slices compared to wild-type slices in both field potential and whole-cell recordings. Consistent with its presynaptic origin, induction of MF-LTP strongly enhanced the excitatory drive onto single CA3 pyramidal cells, with the effect being more pronounced in M1/M3-dKO cells. In an earlier study, we found that the deletion of M2 receptors in mice disinhibits MF-LTP in a similar fashion, suggesting that endogenous acetylcholine employs both M1/M3 and M2 receptors to constrain MF-LTP. Importantly, such synergism was not observed for MF long-term depression (LTD). Low-frequency stimulation, which reliably induced LTD of MF synapses in control slices, failed to do so in M1/M3-dKO slices and gave rise to LTP instead. In striking contrast, loss of M2 receptors augmented LTD when compared to control slices. Taken together, our data demonstrate convergence of M1/M3 and M2 receptors on MF-LTP, but functional divergence on MF-LTD, with the net effect resulting in a well-balanced bidirectional plasticity of the MF-CA3 pyramidal cell synapse.

Stress can be categorized according to physical, psychological and social factors. Exposure to stress produces stress-induced hypersensitivity and forms negative emotions such as anxiety and depression. For example, acute physical stress induced by the elevated open platform (EOP) causes prolonged mechanical hypersensitivity. The anterior cingulate cortex (ACC) is a cortical region involved in pain and negative emotions. Recently, we showed that mice exposed to the EOP changed spontaneous excitatory, but not inhibitory transmission in layer II/III pyramidal neurons of the ACC. However, it is still unclear whether the ACC is involved in the EOP induced mechanical hypersensitivity, and how the EOP alters evoked synaptic transmission on excitatory and inhibitory synaptic transmission in the ACC. In this study, we injected ibotenic acid into the ACC to examine if it was involved in stress-induced mechanical hypersensitivity induced by EOP exposure. Next, by using whole-cell patch-clamp recording from brain slice preparation, we analyzed action potentials and evoked synaptic transmission from layer II/III pyramidal neurons within the ACC. Lesion of the ACC completely blocked the stress-induced mechanical hypersensitivity induced by EOP exposure. Mechanistically, EOP exposure mainly altered evoked excitatory postsynaptic currents such as input-output and paired pulse ratio. Intriguingly, the mice exposed in the EOP also produced low-frequency stimulation induced short-term depression on excitatory synapses in the ACC. These results suggest that the ACC plays a critical role in the modulation of stress-induced mechanical hypersensitivity, possibly through synaptic plasticity on excitatory transmission., Competing Interests: Conflicts of Interest We declare no conflict of interests., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

GWAS have identified numerous genes associated with human cognition but their cell type expression profiles in the human brain are unknown. These genes overlap with human accelerated regions (HARs) implicated in human brain evolution and might act on the same biological processes. Here, we investigated whether these gene sets are expressed in adult human cortical neurons, and how their expression relates to neuronal function and structure. We find that these gene sets are preferentially expressed in L3 pyramidal neurons in middle temporal gyrus (MTG). Furthermore, neurons with higher expression had larger total dendritic length (TDL) and faster action potential (AP) kinetics, properties previously linked to intelligence. We identify a subset of genes associated with TDL or AP kinetics with predominantly synaptic functions and high abundance of HARs., (© 2023. The Author(s).)

The theta rhythm plays a crucial role in synchronizing neural activity during attention and memory processes. However, the mechanisms behind the formation of neural activity during theta rhythm generation remain unknown. To address this, we propose a mathematical model that explains the distribution of interneurons in the CA1 field during the theta rhythm phase. Our model consists of a network of seven types of interneurons in the CA1 field that receive inputs from the CA3 field, entorhinal cortex, and local pyramidal neurons in the CA1 field. By adjusting the parameters of the connections in the model. We demonstrate that it is possible to replicate the experimentally observed phase relations between interneurons and the theta rhythm. Our model predicts that populations of interneurons receive unimodal excitation and inhibition with coinciding peaks, and that excitation dominates to determine the firing dynamics of interneurons., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mysin.)

A synergistic combination of in vitro electrophysiology and multicompartmental modeling of rat CA1 pyramidal neurons identified TRPM4 channels as major drivers of cholinergic modulation of the firing rate during a triangular current ramp, which emulates the bump in synaptic input received while traversing the place field. In control, fewer spikes at lower frequencies are elicited on the down-ramp compared to the up-ramp due to long-term inactivation of the Na V channel. The cholinergic agonist carbachol (CCh) removes or even reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-ramp. CCh application during Schaffer collateral stimulation designed to simulate a ramp produces similar shifts in the center of mass of firing to later in the ramp. The non-specific TRP antagonist flufenamic acid and the TRPM4-specific blockers CBA and 9-phenanthrol, but not the TRPC-specific antagonist SKF96365, reverse the effect of CCh; this implicates the Ca 2+ -activated nonspecific cation current, I CAN , carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca 2+ buffering but not by antagonists for IP 3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca 2+ stores. Pharmacology combined with modeling suggest that [Ca 2+ ] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca 2+ influx during the ramp. Activation of the regenerative inward TRPM4 current in the model qualitatively replicates and provides putative underlying mechanisms for the experimental observations., Competing Interests: CC, CU, CC, SG No competing interests declared, (© 2023, Combe et al.)

The functional heterogeneity of hippocampal CA3 pyramidal neurons has emerged as a key aspect of circuit function. Here, we explored the effects of long-term cholinergic activity on the functional heterogeneity of CA3 pyramidal neurons in organotypic slices obtained from male rat brains. Application of agonists to either AChRs generally, or mAChRs specifically, induced robust increases in network activity in the low-gamma range. Prolonged AChR stimulation for 48 h uncovered a population of hyperadapting CA3 pyramidal neurons that typically fired a single, early action potential in response to current injection. Although these neurons were present in control networks, their proportions were dramatically increased following long-term cholinergic activity. Characterized by the presence of a strong M-current, the hyperadaptation phenotype was abolished by acute application of either M-channel antagonists or the reapplication of AChR agonists. We conclude that long-term mAChR activation modulates the intrinsic excitability of a subset of CA3 pyramidal cells, uncovering a highly plastic cohort of neurons that are sensitive to chronic ACh modulation. Our findings provide evidence for the activity-dependent plasticity of functional heterogeneity in the hippocampus. SIGNIFICANCE STATEMENT The large heterogeneity of neuron types in the brain, each with its own specific functional properties, provides the rich cellular tapestry needed to account for the vast diversity of behaviors. By studying the functional properties of neurons in the hippocampus, a region of the brain involved in learning and memory, we find that exposure to the neuromodulator acetylcholine can alter the relative number of functionally defined neuron types. Our findings suggest that the heterogeneity of neurons in the brain is not a static feature but can be modified by the ongoing activity of the circuits to which they belong., (Copyright © 2023 the authors.)

Brain-state transitions are readily apparent from changes in brain rhythms,1 but are difficult to predict, suggestive that the underlying cause is latent to passive recording methods. Among the most important transitions, clinically, are the starts of seizures. We here show that an 'active probing' approach may have several important benefits for epileptic management, including by helping predict these transitions. We used mice expressing the optogenetic actuator, channelrhodopsin, in pyramidal cells, allowing this population to be stimulated in isolation. Intermittent stimulation at frequencies as low as 0.033 Hz (period = 30 s) delayed the onset of seizure-like events in an acute brain slice model of ictogenesis, but the effect was lost if stimulation was delivered at even lower frequencies (1/min). Notably, active probing additionally provides advance indication of when seizure-like activity is imminent, revealed by monitoring the postsynaptic response to stimulation. The postsynaptic response, recorded extracellularly, showed an all-or-nothing change in both amplitude and duration, a few hundred seconds before seizure-like activity began-a sufficient length of time to provide a helpful warning of an impending seizure. The change in the postsynaptic response then persisted for the remainder of the recording, indicative of a state change from a pre-epileptic to a pro-epileptic network. This occurred in parallel with a large increase in the stimulation-triggered Ca2+ entry into pyramidal dendrites, and a step increase in the number of evoked postsynaptic action potentials, both consistent with a reduction in the threshold for dendritic action potentials. In 0 Mg2+ bathing media, the reduced threshold was not associated with changes in glutamatergic synaptic function, nor of GABAergic release from either parvalbumin or somatostatin interneurons, but simulations indicate that the step change in the optogenetic response can instead arise from incremental increases in intracellular [Cl-]. The change in the response to stimulation was replicated by artificially raising intracellular [Cl-], using the optogenetic chloride pump, halorhodopsin. By contrast, increases in extracellular [K+] cannot account for the firing patterns in the response to stimulation, although this, and other cellular changes, may contribute to ictal initiation in other circumstances. We describe how these various cellular changes form a synergistic network of positive feedback mechanisms, which may explain the precipitous nature of seizure onset. This model of seizure initiation draws together several major lines of epilepsy research as well as providing an important proof-of-principle regarding the utility of open-loop brain stimulation for clinical management of the condition., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pharmacological manipulation of mGluR5 has showed that mGluR5 is implicated in the pathophysiology of anxiety and mGluR5 has been proposed as a potential drug target for anxiety disorders. Nevertheless, the mechanism underlying the mGluR5 involvement in stress-induced anxiety-like behavior remains largely unknown. Here, we found that chronic restraint stress induced anxiety-like behavior and decreased the expression of mGluR5 in hippocampal CA1. Specific knockdown of mGluR5 in hippocampal CA1 pyramidal neurons produced anxiety-like behavior. Furthermore, both chronic restraint stress and mGluR5 knockdown impaired inhibitory synaptic inputs in hippocampal CA1 pyramidal neurons. Notably, positive allosteric modulator of mGluR5 rescued stress-induced anxiety-like behavior and restored the inhibitory synaptic inputs. These findings point to an essential role for mGluR5 in hippocampal CA1 pyramidal neurons in mediating stress-induced anxiety-like behavior., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Traumatic brain injury (TBI) and repetitive head impacts can result in a wide range of neurological symptoms. Despite being the most common neurological disorder in the world, repeat head impacts and TBI do not have any FDA-approved treatments. Single neuron modeling allows researchers to extrapolate cellular changes in individual neurons based on experimental data. We recently characterized a model of high frequency head impact (HFHI) with a phenotype of cognitive deficits associated with decreases in neuronal excitability of CA1 neurons and synaptic changes. While the synaptic changes have been interrogated in vivo, the cause and potential therapeutic targets of hypoexcitability following repetitive head impacts are unknown. Here, we generated in silico models of CA1 pyramidal neurons from current clamp data of control mice and mice that sustained HFHI. We use a directed evolution algorithm with a crowding penalty to generate a large and unbiased population of plausible models for each group that approximated the experimental features. The HFHI neuron model population showed decreased voltage gated sodium conductance and a general increase in potassium channel conductance. We used partial least squares regression analysis to identify combinations of channels that may account for CA1 hypoexcitability after HFHI. The hypoexcitability phenotype in models was linked to A- and M-type potassium channels in combination, but not by any single channel correlations. We provide an open access set of CA1 pyramidal neuron models for both control and HFHI conditions that can be used to predict the effects of pharmacological interventions in TBI models., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The axon initial segment (AIS) is a highly specialized axonal compartment where the action potential is initiated. The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons (PyNs), which likely contributes to their unique spiking properties. However, whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown. Here, we report that in the prelimbic cortex (PL) of the mouse, two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala, possess distinct AIS properties reflected by morphology, ion channel expression, action potential initiation, and axo-axonic synaptic inputs from chandelier cells. Furthermore, projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer. Thus, our study reveals the cortical layer- and axon projection-specific heterogeneity of PyN AISs, which may endow the spiking of various PyN types with exquisite modulation., (© 2023. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Neocortical pyramidal neurons have many dendrites, and such dendrites are capable of, in isolation of one-another, generating a neuronal spike. It is also now understood that there is a large amount of dendritic growth during the first years of a humans life, arguably a period of prodigious learning. These observations inspire the construction of a local, stochastic algorithm based on an earlier stochastic, homeostatic, Hebbian developmental theory. Here we investigate the neurocomputational advantages and limits on this novel algorithm that combines dendritogenesis with supervised adaptive synaptogenesis. Neurons created with this algorithm have enhanced memory capacity, can avoid catastrophic interference (forgetting), and have the ability to unmix mixture distributions. In particular, individual dendrites develop within each class, in an unsupervised manner, to become feature-clusters that correspond to the mixing elements of class-conditional mixture distribution. Error-free classification is demonstrated with input perturbations up to 40%. Although discriminative problems are used to understand the capabilities of the stochastic algorithm and the neuronal connectivity it produces, the algorithm is in the generative class, it thus seems ideal for decisions that require generalization, i.e., extrapolation beyond previous learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A key mode of neuronal communication between distant brain regions is through excitatory synaptic transmission mediated by long-range glutamatergic projections emitted from principal neurons. The long-range glutamatergic projection normally forms numerous en passant excitatory synapses onto both principal neurons and interneurons along its path. Under physiological conditions, the monosynaptic excitatory drive onto postsynaptic principal neurons outweighs disynaptic feedforward inhibition, with the net effect of depolarizing principal neurons. In contrast with this conventional doctrine, here we report that a glutamatergic projection from the hypothalamic supramammillary nucleus (SuM) largely evades postsynaptic pyramidal neurons (PNs), but preferentially target interneurons in the hippocampal CA3 region to predominantly provide feedforward inhibition. Using viral-based retrograde and anterograde tracing and ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording in mice of either sex, we show that SuM projects sparsely to CA3 and provides minimal excitation onto CA3 PNs. Surprisingly, despite its sparse innervation, the SuM input inhibits all CA3 PNs along the transverse axis. Further, we find that SuM provides strong monosynaptic excitation onto CA3 parvalbumin-expressing interneurons evenly along the transverse axis, which likely mediates the SuM-driven feedforward inhibition. Together, our results demonstrate that a novel long-range glutamatergic pathway largely evades principal neurons, but rather preferentially innervates interneurons in a distant brain region to suppress principal neuron activity. Moreover, our findings reveal a new means by which SuM regulates hippocampal activity through SuM-to-CA3 circuit, independent of the previously focused projections from SuM to CA2 or dentate gyrus. SIGNIFICANCE STATEMENT The dominant mode of neuronal communication between brain regions is the excitatory synaptic transmission mediated by long-range glutamatergic projections, which form en passant excitatory synapses onto both pyramidal neurons and interneurons along its path. Under normal conditions, the excitation onto postsynaptic neurons outweighs feedforward inhibition, with the net effect of depolarization. In contrast with this conventional doctrine, here we report that a glutamatergic input from hypothalamic supramammillary nucleus (SuM) largely evades PNs but selectively targets interneurons to almost exclusively provide disynaptic feedforward inhibition onto hippocampal CA3 PNs. Thus, our findings reveal a novel subcortical-hippocampal circuit that enables SuM to regulate hippocampal activity via SuM-CA3 circuit, independent of its projections to CA2 or dentate gyrus., (Copyright © 2023 the authors.)

In the reach and saccade regions of the posterior parietal cortex (PPC), multiregional communication depends on the timing of neuronal activity with respect to beta-frequency (10-30 Hz) local field potential (LFP) activity, termed dual coherence. Neural coherence is believed to reflect neural excitability, whereby spiking tends to occur at a particular phase of LFP activity, but the mechanisms of multiregional dual coherence remain unknown. Here, we investigate dual coherence in the PPC of non-human primates performing eye-hand movements. We computationally model dual coherence in terms of multiregional neural excitability and show that one latent component, a multiregional mode, reflects shared excitability across distributed PPC populations. Analyzing the power in the multiregional mode with respect to different putative cell types reveals significant modulations with the spiking of putative pyramidal neurons and not inhibitory interneurons. These results suggest a specific role for pyramidal neurons in dual coherence supporting multiregional communication in PPC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: How volatile anesthetics work remains poorly understood. Modulations of synaptic neurotransmission are the direct cellular mechanisms of volatile anesthetics in the central nervous system. Volatile anesthetics such as isoflurane may reduce neuronal interaction by differentially inhibiting neurotransmission between GABAergic and glutamatergic synapses. Presynaptic voltage-dependent sodium channels (Na v ), which are strictly coupled with synaptic vesicle exocytosis, are inhibited by volatile anesthetics and may contribute to the selectivity of isoflurane between GABAergic and glutamatergic synapses. However, it is still unknown how isoflurane at clinical concentrations differentially modulates Na v currents between excitatory and inhibitory neurons at the tissue level., Methods: In this study, an electrophysiological recording was applied in cortex slices to investigate the effects of isoflurane on Na v between parvalbumin (PV + ) and pyramidal neurons in PV-cre-tdTomato and/or vglut2-cre-tdTomato mice., Results: Isoflurane at clinically relevant concentrations produced a hyperpolarizing shift in the voltage-dependent inactivation and slowed the recovery time from the fast inactivation in both cellular subtypes. Since the voltage of half-maximal inactivation was significantly depolarized in PV + neurons compared to that of pyramidal neurons, isoflurane inhibited the peak Na v currents in pyramidal neurons more potently than those of PV + neurons (35.95 ± 13.32% vs. 19.24 ± 16.04%, P = 0.036 by the Mann-Whitney test)., Conclusions: Isoflurane differentially inhibits Na v currents between pyramidal and PV + neurons in the prefrontal cortex, which may contribute to the preferential suppression of glutamate release over GABA release, resulting in the net depression of excitatory-inhibitory circuits in the prefrontal cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qiu, Yang, Liu, Zhao, Li, Zhu, Liang and Zhou.)

The relationship between autism spectrum disorder (ASD) and dendritic spine abnormalities is well known, but it is unclear whether the deficits relate to specific neuron types and brain regions most relevant to ASD. Recent genetic studies have identified a convergence of ASD risk genes in deep layer pyramidal neurons of the prefrontal cortex. Here, we use retrograde recombinant adeno-associated viruses to label specifically two major layer V pyramidal neuron types of the medial prefrontal cortex: the commissural neurons, which put the two cerebral hemispheres in direct communication, and the corticopontine neurons, which transmit information outside the cortex. We compare the basal dendritic spines on commissural and corticopontine neurons in WT and KO mice for the ASD risk gene Itgb3, which encodes for the cell adhesion molecule β3 integrin selectively enriched in layer V pyramidal neurons. Regardless of the genotype, corticopontine neurons had a higher ratio of stubby to mushroom spines than commissural neurons. β3 integrin affected selectively spine length in corticopontine neurons. Ablation of β3 integrin resulted in corticopontine neurons lacking long (> 2 μm) thin dendritic spines. These findings suggest that a deficiency in β3 integrin expression compromises specifically immature spines on corticopontine neurons, thereby reducing the cortical territory they can sample. Because corticopontine neurons receive extensive local and long-range excitatory inputs before relaying information outside the cortex, specific alterations in dendritic spines of corticopontine neurons may compromise the computational output of the full cortex, thereby contributing to ASD pathophysiology., (© 2023. The Author(s).)

In primates, the dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices are key nodes in the working memory network. The working memory-related gamma oscillations induced in these areas, predominantly in layer 3, exhibit higher frequency in DLPFC. Although these regional differences in oscillation frequency are likely essential for information transfer between DLPFC and PPC, the mechanisms underlying these differences remain poorly understood. We investigated, in rhesus monkey, the DLPFC and PPC layer 3 pyramidal neuron (L3PN) properties that might regulate oscillation frequency and assessed the effects of these properties simulating oscillations in computational models. We found that GABAAR-mediated synaptic inhibition synchronizes L3PNs in both areas, but analysis of GABAAR mRNA levels and inhibitory synaptic currents suggested similar mechanisms of inhibition-mediated synchrony in DLPFC and PPC. Basal dendrite spine density and AMPAR/NMDAR mRNA levels were higher in DLPFC L3PNs, whereas excitatory synaptic currents were similar between areas. Therefore, synaptically evoked excitation might be stronger in DLPFC L3PNs due to a greater quantity of synapses in basal dendrites, a main target of recurrent excitation. Simulations in computational networks showed that oscillation frequency and power increased with increasing recurrent excitation, suggesting a mechanism by which the DLPFC-PPC differences in oscillation properties are generated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions. SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs., (Copyright © 2023 Giordano, Alia et al.)

Disruption of circadian rhythms, such as shift work and jet lag, are associated with negative physiological and behavioral outcomes, including changes in affective state, learning and memory, and cognitive function. The prefrontal cortex (PFC) is heavily involved in all of these processes. Many PFC-associated behaviors are time-of-day dependent, and disruption of daily rhythms negatively impacts these behavioral outputs. Yet how disruption of daily rhythms impacts the fundamental function of PFC neurons, and the mechanism(s) by which this occurs, remains unknown. Using a mouse model, we demonstrate that the activity and action potential dynamics of prelimbic PFC neurons are regulated by time-of-day in a sex specific manner. Further, we show that postsynaptic K + channels play a central role in physiological rhythms, suggesting an intrinsic gating mechanism mediating physiological activity. Finally, we demonstrate that environmental circadian desynchronization alters the intrinsic functioning of these neurons independent of time-of-day. These key discoveries demonstrate that daily rhythms contribute to the mechanisms underlying the essential physiology of PFC circuits and provide potential mechanisms by which circadian disruption may impact the fundamental properties of neurons., (© 2023. The Author(s).)

Human beings are living longer than ever before and the cognitive decline experienced by aged adults, such as compromise in cognitive flexibility, has been attracting more and more attention. One such example is the aging-related impairment of memory extinction. However, its underlying neural basis, especially its functional basis at the synapse level, is largely unknown. This study verifies that Pavlovian contextual fear memory extinction is impaired in aged mice. A large body of previous studies has shown that the infralimbic prefrontal cortex (ilPFC) plays a pivotal role in memory extinction. Correspondingly, this study reveals an aging-related reduction in the efficacy of excitatory synaptic transmission onto the ilPFC pyramidal neurons via electrophysiology recordings. This study further suggests that this reduced excitation potentially contributes to the aging-related impairment of contextual fear memory extinction: chemogenetically suppressing the activity of the ilPFC pyramidal neurons in young mice impairs contextual fear memory extinction, whereas chemogenetically compensating for the reduced excitation of the ilPFC pyramidal neurons in aged mice restores contextual fear memory extinction. This study identifies a functional synaptic plasticity in the ilPFC pyramidal neurons that potentially contributes to the aging-related impairment of contextual fear memory extinction, which would potentially help to develop a therapy to treat related cognitive decline in aged human adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is essential for elucidating the mechanism of memory formation and recall. For decades, the trisynaptic circuit (entorhinal cortex layer II-dentate gyrus - CA3-CA1) has been considered the neural network substrate responsible for learning and memory. Recently, CA2 has emerged as an important area in the hippocampal circuitry, with distinct functions from those of CA3. In this article, we review the historical definition of the hippocampal area CA2 and the differential projection patterns between CA2 and CA3 pyramidal neurons. We provide a concise and comprehensive map of CA2 outputs by comparing (1) ipsi versus contra projections, (2) septal versus temporal projections, and (3) lamellar structures of CA2 and CA3 pyramidal neurons., (© 2023 Wiley Periodicals LLC.)

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood. The prefrontal cortex (PFC) is known to mediate EF and WM and is an area that shows a vulnerability to age-related alterations in neuronal morphology. In the current study, we show that performance on EF and WM tasks exhibited significant changes with age, and these impairments correlate with changes in biophysical properties of layer 3 (L3) pyramidal neurons in lateral LPFC (LPFC). Specifically, there was a significant age-related increase in excitability of L3 LPFC pyramidal neurons, consistent with previous studies. Further, this age-related hyperexcitability of LPFC neurons was significantly correlated with age-related decline on a task of WM, but not an EF task. The current study characterizes age-related performance on tasks of WM and EF and provides insight into the neural substrates that may underlie changes in both WM and EF with age., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Tinnitus affects roughly 15%-20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage to the auditory periphery, resulting in a cascade of maladaptive plastic changes at multiple levels of the central auditory neuraxis as well as limbic and non-auditory cortical centres. Using a well-established condition-suppression model of tinnitus, we measured tinnitus-related changes in the microcircuits of excitatory/inhibitory neurons onto layer 5 pyramidal neurons (PNs), as well as changes in the excitability of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1). Patch-clamp recordings from PNs in A1 slices showed tinnitus-related increases in spontaneous excitatory postsynaptic currents (sEPSCs) and decreases in spontaneous inhibitory postsynaptic currents (sIPSCs). Both measures could be correlated to the rat's behavioural evidence of tinnitus. Tinnitus-related changes in PN excitability were independent of changes in A1 excitatory or inhibitory cell numbers. VIP neurons, part of an A1 local circuit that can control the excitation of layer 5 PNs via disinhibitory mechanisms, showed significant tinnitus-related increases in excitability that directly correlated with the rat's behavioural tinnitus score. That PN and VIP changes directly correlated to tinnitus behaviour suggests an important role in A1 tinnitus pathology. Tinnitus-related A1 changes were similar to findings in studies of neuropathic pain in somatosensory cortex suggesting a common pathology of these troublesome perceptual impairments. Improved understanding between excitatory, inhibitory and disinhibitory sensory cortical circuits can serve as a model for testing therapeutic approaches to the treatment of tinnitus and chronic pain. KEY POINTS: We identified tinnitus-related changes in synaptic function of specific neuronal subtypes in a reliable animal model of tinnitus. The findings show direct and indirect tinnitus-related losses of normal inhibitory function at A1 layer 5 pyramidal cells, and increased VIP excitability. The findings are similar to what has been shown for neuropathic pain suggesting that restoring normal inhibitory function at synaptic inputs onto A1 pyramidal neurons (PNs) could conceptually reduce tinnitus discomfort., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Uncovering the wiring rules employed by neurons during development represents a formidable challenge with important repercussions for neurodevelopmental disorders. Chandelier cells (ChCs) are a singular GABAergic interneuron type, with a unique morphology, that have recently begun to shed light on the rules that drive the formation and plasticity of inhibitory synapses. This review will focus on the wealth of recent data charting the emergence of synapses formed by ChCs onto pyramidal cells, from the molecules involved to the plasticity of these connections during development., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The structures of dendrites and axons form the basis for the connectivity of neural network, but their precise relationship at single-neuron level remains unclear. Here we report the complete dendrite and axon morphology of nearly 2,000 neurons in mouse prefrontal cortex (PFC). We identified morphological variations of somata, dendrites and axons across laminar layers and PFC subregions and the general rules of somatodendritic scaling with cytoarchitecture. We uncovered 24 morphologically distinguishable dendrite subtypes in 1,515 pyramidal projection neurons and 405 atypical pyramidal projection neurons and spiny stellate neurons with unique axon projection patterns. Furthermore, correspondence analysis among dendrites, local axons and long-range axons revealed coherent morphological changes associated with electrophysiological phenotypes. Finally, integrative dendrite-axon analysis uncovered the organization of potential intra-column, inter-hemispheric and inter-column connectivity among projection neuron types in PFC. Together, our study provides a comprehensive structural repertoire for the reconstruction and analysis of PFC neural network., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Pannexin-1 (Panx1) hemichannel is a non-selective transmembrane channel that may play important roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Although recent evidence shows that the Panx1 hemichannel is involved in controlling excitatory synaptic transmission, the role of Panx1 in inhibitory transmission remains unknown. Here, we studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. We reported that blockage of the Panx1 hemichannel with the mimetic peptide 10 Panx1 increases the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which results in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Our finding provides important insight unveiling that Panx1 can strongly influence the overall neuronal excitability and play a key role in shaping synaptic changes affecting the amplitude and direction of plasticity, as well as learning and memory processes.