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Neuronal processing of external sensory input is shaped by internally generated top-down information. In the neocortex, top-down projections primarily target layer 1, which contains NDNF (neuron-derived neurotrophic factor)-expressing interneurons and the dendrites of pyramidal cells. Here, we investigate the hypothesis that NDNF interneurons shape cortical computations in an unconventional, layer-specific way, by exerting presynaptic inhibition on synapses in layer 1 while leaving synapses in deeper layers unaffected. We first confirm experimentally that in the auditory cortex, synapses from somatostatin-expressing (SOM) onto NDNF neurons are indeed modulated by ambient Gamma-aminobutyric acid (GABA). Shifting to a computational model, we then show that this mechanism introduces a distinct mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons. This motif can control inhibition in a layer-specific way and introduces competition between NDNF and SOM interneurons for dendritic inhibition onto pyramidal cells on different timescales. NDNF interneurons can thereby control cortical information flow by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition., Competing Interests: Competing interests statement:The authors declare no competing interest.

There are various forms of stress including; physical, psychological and social stress. Exposure to physical stress can lead to physical sensations (e.g. hyperalgesia) and negative emotions including anxiety and depression in animals and humans. Recently, our studies in mice have shown that acute physical stress induced by the elevated open platform (EOP) can provoke long-lasting mechanical hypersensitivity. This effect appears to be related to activity in the anterior cingulate cortex (ACC) at the synaptic level. Indeed, EOP exposure induces synaptic plasticity in layer II/III pyramidal neurons from the ACC. However, it is still unclear whether or not EOP exposure alters intrinsic properties and synaptic transmission in layer V pyramidal neurons. This is essential because these neurons are known to be a primary output to subcortical structures which may ultimately impact the behavioral stress response. Here, we studied both intrinsic properties and excitatory/inhibitory synaptic transmission by using whole-cell patch-clamp method in brain slice preparations. The EOP exposure did not change intrinsic properties including resting membrane potentials and action potentials. In contrast, EOP exposure suppressed the frequency of miniature and spontaneous excitatory synaptic transmission with an alteration of kinetics of AMPA/GluK receptors. EOP exposure also reduced evoked synaptic transmission induced by electrical stimulation. Furthermore, we investigated projection-selective responses of the mediodorsal thalamus to the layer V ACC neurons. EOP exposure produced short-term depression in excitatory synaptic transmission on thalamo-ACC projections. These results suggest that the EOP stress provokes abnormal excitatory synaptic transmission in layer V pyramidal neurons of the ACC., 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 © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Norepinephrine (NE) released from locus coeruleus (LC) noradrenergic (NAergic) neurons plays a pivotal role in the regulation of olfactory behaviors. However, the precise circuits and receptor mechanisms underlying this function are not well understood. Here, in DBH-Cre mice model, we show that LC NAergic neurons project directly to both anterior piriform cortex (aPC) and the olfactory bulb (OB). By using pharmacological and optogenetic manipulations in vitro and in vivo, we found that NE reduces the excitability of aPC pyramidal neurons directly via α2 receptors and that it bidirectionally regulates the activity of OB mitral cells via modulation of inhibitory inputs. Activation of the NAergic projection reduced both spontaneous and odor-evoked activity in the aPC/OB in awake mice, enhanced the odor-decoding ability of the aPC, and decreased the odor-decoding ability of the OB. Furthermore, activation of LC-aPC/OB NAergic projections accelerated odor discrimination and specific inactivation of the LC-aPC/OB NAergic pathway impaired olfactory detection and discrimination. These findings identify the mechanism underlying NAergic modulation of the aPC/OB and elucidate its role in odor processing and olfactory behaviors., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Patients with bipolar disorder (BD) demonstrate episodic memory deficits, which may be hippocampal-dependent and may be attenuated in lithium responders. Induced pluripotent stem cell-derived CA3 pyramidal cell-like neurons show significant hyperexcitability in lithium-responsive BD patients, while lithium nonresponders show marked variance in hyperexcitability. We hypothesize that this variable excitability will impair episodic memory recall, as assessed by cued retrieval (pattern completion) within a computational model of the hippocampal CA3., Methods: We simulated pattern completion tasks using a computational model of the CA3 with different degrees of pyramidal cell excitability variance. Since pyramidal cell excitability variance naturally leads to a mix of hyperexcitability and hypoexcitability, we also examined what fraction (hyper- vs. hypoexcitable) was predominantly responsible for pattern completion errors in our model., Results: Pyramidal cell excitability variance impaired pattern completion (linear model β = -2.00, SE = 0.03, p < 0.001). The effect was invariant to all other parameter settings in the model. Excitability variance, specifically hyperexcitability, increased the number of spuriously active neurons, increasing false alarm rates and producing pattern completion deficits. Excessive inhibition also induces pattern completion deficits by limiting the number of correctly active neurons during pattern retrieval., Conclusions: Excitability variance in CA3 pyramidal cell-like neurons observed in lithium nonresponders may predict pattern completion deficits in these patients. These cognitive deficits may not be fully corrected by medications that minimize excitability. Future studies should test our predictions by examining behavioral correlates of pattern completion in lithium-responsive and -nonresponsive BD patients., (© 2025 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680 +/+ ) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680 +/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680 +/+ mice., Competing Interests: Conflict of interest: The authors declare that there are no conflicts of interest., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

'Cellular psychology' is a new field of inquiry that studies dendritic mechanisms for adapting mental events to the current context, thus increasing their coherence, flexibility, effectiveness, and comprehensibility. Apical dendrites of neocortical pyramidal cells have a crucial role in cognition - those dendrites receive input from diverse sources, including feedback, and can amplify the cell's feedforward transmission if relevant in that context. Specialized subsets of inhibitory interneurons regulate this cooperative context-sensitive processing by increasing or decreasing amplification. Apical input has different effects on cellular output depending on whether we are awake, deeply asleep, or dreaming. Furthermore, wakeful thought and imagery may depend on apical input. High-resolution neuroimaging in humans supports and complements evidence on these cellular mechanisms from other mammals., Competing Interests: Declaration of interests No interests are declared., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

The hypothesis that the hippocampal theta rhythm consists of inhibitory postsynaptic potentials (IPSPs) was critical for understanding the theta rhythm. The dominant views in the early 1980s were that intracellularly recorded theta consisted of excitatory postsynaptic potentials (EPSPs) with little participation by IPSPs, and that IPSPs generated a closed monopolar field in the hippocampus. I (Leung) conceived of a new model for generation of the hippocampal theta rhythm, with theta-rhythmic IPSPs as an essential component, and thus sought to reinvestigate the relation between theta and IPSPs quantitatively with intracellular and extracellular recordings. The intracellular recordings were performed by Leung and Yim in the laboratory of Kris Krnjević at McGill University. Using protocols of passing steady-state holding currents and injection of chloride ions, the intracellular theta and IPSP in a CA1 neuron typically showed the same reversal potential and correlated change in amplitude. Low-intensity stimulation of the alveus evoked an antidromic action potential in CA1 neurons, identifying them as pyramidal cells with output axons in the alveus, which then activated a feedback IPSP with almost no excitatory component. Theta-rhythmic somatic inhibition, together with phase-shifted theta-rhythmic distal apical dendritic excitation were proposed as the two dipoles that generate a gradual extracellular theta phase shift in the CA1 apical dendritic layer. The distal apical excitation driven by the entorhinal cortex was proposed to be atropine-resistant and dominated during walking in rats. Other than serving a conventional role in limiting excitation, rhythmic proximal inhibition and distal dendritic excitation provide varying phasic modulation along the soma-dendritic axis of pyramidal cells, resulting in theta phase-dependent synaptic plasticity and gamma oscillations, which are likely involved in cognitive processing., (© 2024 Wiley Periodicals LLC.)

It is well recognized that changes in the extracellular concentration of calcium ions influence the excitability of neurons, yet what mechanism(s) mediate these effects is still a matter of debate. Using patch-clamp recordings from rat hippocampal CA1 pyramidal neurons, we examined the contribution of G-proteins and intracellular calcium-dependent signaling mechanisms to changes in intrinsic excitability evoked by altering the extracellular calcium concentration from physiological (1.2 mM) to a commonly used experimental (2 mM) level. We find that the inhibitory effect on intrinsic excitability of calcium ions is mainly expressed as an increased threshold for action potential firing (with no significant effect on resting membrane potential) that is not blocked by either the G-protein inhibitor GDPβS or the calcium chelator BAPTA. Our results therefore argue that in the concentration range studied, G-protein coupled calcium-sensing receptors, non-selective cation conductances, and intracellular calcium signaling pathways are not involved in mediating the effect of extracellular calcium ions on intrinsic excitability. Analysis of the derivative of the action potential, dV/dt versus membrane potential, indicates a current shift towards more depolarized membrane potentials at the higher calcium concentration. Our results are thus consistent with a mechanism in which extracellular calcium ions act directly on the voltage-gated sodium channels by neutralizing negative charges on the extracellular surface of these channels to modulate the threshold for action potential activation., (© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Both alcohol use disorder (AUD) and cognitive decline include disruption in the balance of excitation and inhibition in the cortex, but the potential role of alcohol use on excitation and inhibition on the aging brain is unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on cognitive disorder progression, such as Alzheimer's Disease, in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Learning alters cortical representations and improves perception. Apical tuft dendrites in cortical layer 1, which are unique in their connectivity and biophysical properties, may be a key site of learning-induced plasticity. We used both two-photon and SCAPE microscopy to longitudinally track tuft-wide calcium spikes in apical dendrites of layer 5 pyramidal neurons in barrel cortex as mice learned a tactile behavior. Mice were trained to discriminate two orthogonal directions of whisker stimulation. Reinforcement learning, but not repeated stimulus exposure, enhanced tuft selectivity for both directions equally, even though only one was associated with reward. Selective tufts emerged from initially unresponsive or low-selectivity populations. Animal movement and choice did not account for changes in stimulus selectivity. Enhanced selectivity persisted even after rewards were removed and animals ceased performing the task. We conclude that learning produces long-lasting realignment of apical dendrite tuft responses to behaviorally relevant dimensions of a task., Competing Interests: SB, KP, CP, RB No competing interests declared, EH A patent related to the SCAPE microscopy technique used in Figure 4 was issued on December 31st 2013, and the author has licensed the technology, (© 2024, Benezra et al.)

Itch serves as a self-protection mechanism against harmful external agents, whereas uncontrolled and persistent itch severely influences the quality of life of patients and aggravates their diseases. Unfortunately, the existing treatments are largely ineffective. The current difficulty in treatment may be closely related to the fact that the central neural mechanisms underlying itch processing, especially descending inhibition of itch, are poorly understood. Here, we demonstrate that an excitatory descending neural circuit from rostral anterior cingulate cortex pyramidal (rACC Py ) neurons to periaqueductal gray GABAergic (PAG GABA ) neurons plays a key role in the inhibition of itch. The activity of itch-tagged rACC Py neurons decreases during the itch-evoked scratching period. Artificial activation or inhibition of the neural circuits significantly impairs or enhances itch processing, respectively. Thus, an excitatory neural circuit is identified as playing a crucial inhibitory role in descending regulation of itch, suggesting that it could be a potential target for treating itch., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

One of the most fundamental laws of physics is the principle of least action. Motivated by its predictive power, we introduce a neuronal least-action principle for cortical processing of sensory streams to produce appropriate behavioral outputs in real time. The principle postulates that the voltage dynamics of cortical pyramidal neurons prospectively minimizes the local somato-dendritic mismatch error within individual neurons. For output neurons, the principle implies minimizing an instantaneous behavioral error. For deep network neurons, it implies the prospective firing to overcome integration delays and correct for possible output errors right in time. The neuron-specific errors are extracted in the apical dendrites of pyramidal neurons through a cortical microcircuit that tries to explain away the feedback from the periphery, and correct the trajectory on the fly. Any motor output is in a moving equilibrium with the sensory input and the motor feedback during the ongoing sensory-motor transform. Online synaptic plasticity reduces the somatodendritic mismatch error within each cortical neuron and performs gradient descent on the output cost at any moment in time. The neuronal least-action principle offers an axiomatic framework to derive local neuronal and synaptic laws for global real-time computation and learning in the brain., Competing Interests: WS, DD, AK, BE, JJ, YB, JS, MP No competing interests declared, (© 2023, Senn, Dold et al.)

Background: Although there has been limited research into the perturbation of electrophysiological activity in the brain after ischemia, the activity signatures during ischemia and reperfusion remain to be fully elucidated. We aim to comprehensively describe these electrophysiological signatures and interrogate their correlation with ischemic damage during global cerebral ischemia and reperfusion., Methods and Results: We used the 4-vessel occlusion method of inducing global cerebral ischemia in rats. We used in vivo electrophysiological techniques to simultaneously record single units, scalp electroencephalogram, and local field potentials in awake animals. Neuronal damage and astrocyte reactivation were examined by immunofluorescence, immunoblotting, and quantitative real-time reverse-transcription polymerase chain reaction under chemogenetic inhibition of glutamatergic neurons. Electroencephalogram/local field potentials power and phase-amplitude coupling of the theta and low-gamma bands were reduced during ischemia and the acute phase of reperfusion. The firing rate of single units was enhanced by ischemia-reperfusion, and the phase relationship between the local field potentials theta band and neuronal firing was altered. Precise inhibition of hippocampus CA1 pyramidal neuron hyperactivity by chemogenetics rescued the firing dysfunction, ischemic neuronal damage, and A1 astrocyte activation., Conclusions: Our results provide a comprehensive description of the characteristics of electrophysiological activity that accompany ischemia-reperfusion and highlight the significance of this activity in ischemic damage.

Synaptic mechanisms that contribute to human memory consolidation remain largely unexplored. Consolidation critically relies on sleep. During slow wave sleep, neurons exhibit characteristic membrane potential oscillations known as UP and DOWN states. Coupling of memory reactivation to these slow oscillations promotes consolidation, though the underlying mechanisms remain elusive. Here, we performed axonal and multineuron patch-clamp recordings in acute human brain slices, obtained from neurosurgeries, to show that sleep-like UP and DOWN states modulate axonal action potentials and temporarily enhance synaptic transmission between neocortical pyramidal neurons. Synaptic enhancement by UP and DOWN state sequences facilitates recruitment of postsynaptic action potentials, which in turn results in long-term stabilization of synaptic strength. In contrast, synapses undergo lasting depression if presynaptic neurons fail to recruit postsynaptic action potentials. Our study offers a mechanistic explanation for how coupling of neural activity to slow waves can cause synaptic consolidation, with potential implications for brain stimulation strategies targeting memory performance., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Impairments in synaptic dynamics and stability are observed both in neurodegenerative disorders and in the healthy aging cortex, which exhibits elevated dendritic spine turnover and decreased long-term stability of excitatory connections at baseline, as well as an altered response to plasticity induction. In addition to the discrete gain and loss of synapses, spines also change in size and strength both during learning and in the absence of neural activity, and synaptic volume has been associated with stability and incorporation into memory traces. Furthermore, intrinsic dynamics, an apparently stochastic component of spine volume changes, may serve as a homeostatic mechanism to prevent stabilization of superfluous connections. However, the effects of age on modulation of synaptic weights remain unknown. Using two-photon excitation (2PE) microscopy of spines during chemical plasticity induction in vitro and analyzing longitudinal in vivo 2PE images after a plasticity-inducing manipulation, we characterize the effects of age on volumetric changes of spines of the apical tuft of layer 5 pyramidal neurons of mouse primary somatosensory cortex. Aged mice exhibit decreased volumetric volatility and delayed rearrangement of synaptic weights of persistent connections, as well as greater susceptibility to spine shrinkage in response to chemical long-term depression. These results suggest a deficit in the aging brain's ability to fine-tune synaptic weights to properly incorporate and retain novel memories. This research provides the first evidence of alterations in spine volumetric dynamics in healthy aging and may support a model of impaired processing and learning in the aged somatosensory system., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Here we describe a type of depolarising plateau potentials (PPs; sustained depolarisations outlasting the stimuli) in layer 2/3 pyramidal cells (L2/3PC) in rat prefrontal cortex (PFC) slices, using whole-cell somatic recordings. To our knowledge, this PP type has not been described before. In particular, unlike previously described plateau potentials that originate in the large apical dendrite of L5 cortical pyramidal neurons, these L2/3PC PPs are generated independently of the apical dendrite. Thus, surprisingly, these PPs persisted when the apical dendrite was cut off (~50 μm from the soma), and were sustained by local calcium application only to the somatic and basal dendritic compartments. The prefrontal L2/3PCs have been postulated to have a key role in consciousness, according to the Global Neuronal Workspace Theory: their long-range cortico-cortical connections provide the architecture required for the "global work-space", "ignition", amplification, and sustained, reverberant activity, considered essential for conscious access. The PPs in L2/3PCs caused sustained spiking that profoundly altered the input-output relationships of these neurons, resembling the sustained activity suggested to underlie working memory and the mechanism underlying "behavioural time scale synaptic plasticity" in hippocampal pyramidal cells. The non-apical L2/3 PPs depended on metabotropic cholinergic (mAChR) or glutamatergic (mGluR) modulation, which is probably essential also for conscious brain states and experience, in both wakefulness and dreaming. Pharmacological tests indicated that the non-apical L2/3 PPs depend on transient receptor potential (TRP) cation channels, both TRPC4 and TRPC5, and require external calcium (Ca2+) and internal Ca2+ stores, but not voltage-gated Ca2+ channels, unlike Ca2+-dependent PPs in other cortical pyramidal neurons. These L2/3 non-apical plateau potentials may be involved in prefrontal functions, such as access consciousness, working memory, and executive functions such as planning, decision-making, and outcome prediction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hagger-Vaughan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During neuronal activity, the extracellular concentration of potassium ions ([K+]o) increases substantially above resting levels, yet it remains unclear what role these [K+]o changes play in the dendritic integration of synaptic inputs. We here used mathematical formulations and biophysical modeling to explore the role of synaptic activity-dependent K+ changes in dendritic segments of a visual cortex pyramidal neuron, receiving inputs tuned to stimulus orientation. We found that the spatial arrangement of inputs dictates the magnitude of [K+]o changes in the dendrites: Dendritic segments receiving similarly tuned inputs can attain substantially higher [K+]o increases than segments receiving diversely tuned inputs. These [K+]o elevations in turn increase dendritic excitability, leading to more robust and prolonged dendritic spikes. Ultimately, these local effects amplify the gain of neuronal input-output transformations, causing higher orientation-tuned somatic firing rates without compromising orientation selectivity. Our results suggest that local, activity-dependent [K+]o changes in dendrites may act as a "volume knob" that determines the impact of synaptic inputs on feature-tuned neuronal firing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nordentoft et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Single-photon optogenetics enables precise, cell-type-specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bears promise for brain-machine interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cats of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than the preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers., (Copyright © 2024 the authors.)

Serving as an integral node for cognitive processing and value-based decision-making, the orbitofrontal cortex (OFC) plays a multifaceted role in associative learning and reward-driven behaviours through its widespread synaptic integration with both subcortical structures and sensory cortices. Despite the OFC's robust innervation of the olfactory cortex, the functional implications and underlying mechanisms of this top-down influence remain largely unexplored. In this study, we demonstrated that the OFC formed both direct excitatory and indirect inhibitory synaptic connections with pyramidal neurons in the anterior piriform cortex (aPC). OFC projection predominantly regulated spontaneous and odour-evoked excitatory activity in the aPC of awake mice. Importantly, suppression of this OFC-aPC projection disrupted olfactory discrimination learning, potentially due to a consequent decrease in the excitability of aPC principal output neurons following inhibition of this projection. Whole-cell recordings revealed that olfactory learning increased the intrinsic excitability of aPC neurons while concurrently decreasing OFC input to these neurons. These findings underscore the pivotal influence of orbitofrontal modulation over the olfactory cortex in the context of olfactory learning and provide insight into the associated neurophysiological mechanisms. KEY POINTS: The orbitofrontal cortex (OFC) densely innervates the anterior piriform cortex (aPC) through direct excitatory synaptic connections. The OFC regulates both spontaneous and odour-evoked excitatory activities in the aPC of awake mice. Inhibition of OFC projections disrupts olfactory discrimination learning, probably due to reduced excitability of aPC main output neurons. Following olfactory learning, the intrinsic excitability of aPC neurons increases while the OFC-aPC input decreases, highlighting the importance of adaptable OFC input for olfactory learning. These results provide new perspectives on how the OFC's top-down control modulates sensory integration and associative learning., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Social isolation during adolescence negatively impacts the development of adult social behaviors. However, the exact link between social experiences during adolescence and social behaviors in adulthood is not fully understood. In the present study, we investigated how isolation during juvenility affects harm avoidance behavior in a mouse model of juvenile social isolation. We found that mice subjected to social isolation as juveniles display atypical harm avoidance behaviors and that neurons in the anterior cingulate cortex are involved in these abnormal behaviors. Furthermore, we discovered that the chemogenetic activation of anterior cingulate cortex pyramidal neurons can rescue impaired harm-avoidance behaviors in these mice. Our findings provide valuable insights into the potential mechanisms underlying the impact of social experiences on behavior and brain function. Understanding how social isolation during crucial developmental periods can lead to alterations in behavior opens up new avenues for exploring therapeutic interventions for neuropsychiatric disorders characterized by impaired prosocial behaviors., Competing Interests: Declaration of competing interest The authors have no relevant financial or non‐financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although the actions of dopamine throughout the brain are clearly linked to motivation and cognition, the specific role(s) of dopamine in the CA1 subfield of the ventral hippocampus (vH) is unresolved. Prior preclinical studies suggest that dopamine D 3 receptors (D 3 Rs) expressed on CA1 pyramidal cells exhibit a unique capacity to modulate mechanisms of long-term synaptic plasticity, but less is known about how interneuronal inputs modulate these cells. We hypothesized that inputs from μ-opioid receptor (MOR)-expressing inhibitory interneurons selectively modulate the activity of postsynaptic D 3 Rs expressed on CA1 principal cells to shape neurotransmission in the rat vH. We used the whole cell voltage-clamp technique to test this hypothesis by measuring evoked inhibitory postsynaptic currents (eIPSCs) from CA1 principal cells in vH slices or GABA A currents from acutely dissociated vH neurons. The eIPSC response recorded from CA1 neurons in vH slices was inhibited by either the MOR agonist DAMGO or the D 3 R agonist PD128907, but pretreatment with DAMGO occluded any further inhibition by PD128907. GABA A currents measured in acutely dissociated vH CA1 neurons were inhibited by D 3 R activation via PD128907, consistent with postsynaptic localization of D 3 receptors. Kinetic alterations induced by the neuromodulatory agonists are consistent with selective targeting of postsynaptic D 3 Rs expressed on CA1 principal cells by MOR-expressing GABAergic inputs. Our findings suggest that postsynaptic D 3 R-mediated modulation of MOR-expressing GABAergic inputs is a site at which dopaminergic and opioidergic activity may contribute to disinhibition of vH excitatory neurotransmission and, thus, influence critical physiological processes such as synaptic plasticity and network oscillations. NEW & NOTEWORTHY We report that the activity of an inhibitory synapse on CA1 pyramidal cells in the rat ventral hippocampus is shaped by heterogeneous neuromodulators. Specifically, postsynaptic dopamine D 3 receptors on ventral hippocampal CA1 pyramidal neurons are selectively targeted by an inhibitory input from µ-opioid receptor-expressing GABAergic terminals.

Hippocampal CA3 is central to memory formation and retrieval. Although various network mechanisms have been proposed, direct evidence is lacking. Using intracellular V m recordings and optogenetic manipulations in behaving mice, we found that CA3 place-field activity is produced by a symmetric form of behavioral timescale synaptic plasticity (BTSP) at recurrent synapses among CA3 pyramidal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not the DG was required to update place cell activity based on the animal's movement. These data were captured by a computational model that used BTSP and an external updating input to produce attractor dynamics under online learning conditions. Theoretical analyses further highlight the superior memory storage capacity of such networks, especially when dealing with correlated input patterns. This evidence elucidates the cellular and circuit mechanisms of learning and memory formation in the hippocampus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hippocampus is a higher-order brain structure responsible for encoding new episodic memories and predicting future outcomes. In the absence of external stimuli, neurons in the hippocampus track elapsed time, distance traveled, and other idiothetic variables. To this day, the exact determinants of idiothetic representations during free navigation remain unclear. Here, we developed unsupervised approaches to extract population and single-cell properties of more than 30,000 CA1 pyramidal neurons in freely moving mice. We find that spatiotemporal representations are composed of a mixture of idiothetic and allocentric information, the balance of which is dictated by task demand and environmental conditions. Additionally, a subset of CA1 pyramidal neurons encodes the spatiotemporal distance to rewards. Finally, distance and time information is integrated postsynaptically in the lateral septum, indicating that these high-level representations are effectively integrated in downstream neurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Giant Depolarizing Potentials (GDPs) and Early Sharp Waves (eSPWs) are the major patterns of neuronal network activity in the developing hippocampus of neonatal rodents in vitro and in vivo, respectively. Because of certain similarities in their electrographic traits, GDPs and eSPWs were originally considered as homologous patterns. Here, we compared electrographic features and current density profiles of field GDPs (fGDPs) and eSPWs using extracellular multisite silicon probe recordings from neonatal rat CA1 hippocampus. We found that fGDPs in hippocampal slices were much less in amplitude than eSPWs, and were characterized by electronegativity and current sinks in CA1 pyramidal cell layer and stratum radiatum, and positive waves/sources in stratum lacunosum-moleculare. eSPWs in vivo showed a remarkably different depth profile, with positivity and current source in the CA1 pyramidal cell layer, and negativity/sinks in stratum radiatum and stratum lacunosum-moleculare. Current sinks of CA3-evoked responses corresponded to sinks of fGDPs and eSPWs in the stratum radiatum. However, current sinks of entorhinal inputs - evoked responses in stratum lacunosum-moleculare, which were characteristic of eSPWs, were absent in fGDPs. In addition, fGDPs more strongly modulated neuronal firing in CA1 compared to eSPWs. Thus, we show important differences in the electrographic properties of GDPs and eSPWs that challenge the homology of these two activity patterns., Competing Interests: Declaration of Competing interest 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 © 2024 Elsevier Inc. All rights reserved.)

The hypothalamic supramammillary nucleus (SuM) projects heavily to the hippocampus to regulate hippocampal activity and plasticity. Although the projections from the SuM to the dentate gyrus (DG) and CA2 have been extensively studied, whether the SuM projects to CA1, the main hippocampal output region, is unclear. Here, we report a glutamatergic pathway from the SuM that selectively excites CA1 interneurons in the border between the stratum radiatum (SR) and the stratum lacunosum-moleculare (SLM). We find that the SuM projects selectively to a narrow band in the CA1 SR/SLM and monosynaptically excites SR/SLM interneurons, including vasoactive intestinal peptide-expressing (VIP + ) and neuron-derived neurotrophic factor-expressing (NDNF + ) cells, but completely avoids making monosynaptic contacts with CA1 pyramidal neurons (PNs) or parvalbumin-expressing (PV + ) or somatostatin-expressing (SOM + ) cells. Moreover, SuM activation drives spikes in most SR/SLM interneurons to suppress CA1 PN excitability. Taken together, our findings reveal that the SuM can directly regulate hippocampal output region CA1, bypassing CA2, CA3, and the DG., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Odors are key signals for guiding spatial behaviors such as foraging and navigation in rodents. Recent findings reveal that odor representations in the piriform cortex (PCx) also encode spatial context information. However, the brain origins of this information and its integration into PCx microcircuitry remain unclear. This study investigates the lateral entorhinal cortex (LEC) as a potential source of spatial contextual information affecting the PCx microcircuit and its olfactory responses. Using mice brain slices, we performed patch-clamp recordings on superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to observe their impact on PCx activity. Results show that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons due to higher monosynaptic connectivity. LEC inputs also differentially affect inhibitory circuits, activating PV while suppressing SOM interneurons. Studying the interaction between LEC inputs and sensory signals from the lateral olfactory tract (LOT) revealed that simultaneous LEC and LOT activation increases spiking in SP and DP neurons, with DP neurons showing a sharpened response due to LEC-induced inhibition that suppresses delayed LOT-evoked spikes. This suggests a regulatory mechanism where LEC inputs inhibit recurrent activity by activating PV interneurons. Our findings demonstrate that LEC afferents reconfigure PCx activity, aiding the understanding of how odor objects form within the PCx by integrating olfactory and nonolfactory information., Competing Interests: Competing interests statement:The authors declare no competing interest.

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models"., Competing Interests: Declaration of Competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neurodevelopmental abnormalities are considered to be one of the important causes of schizophrenia. The offspring of methylazoxymethanol acetate (MAM)-exposed mice are recognized for the dysregulation of neurodevelopment and are well-characterized with schizophrenia-like phenotypes. However, the inhibition-related properties of the medial prefrontal cortex (mPFC) and hippocampus throughout adolescence and adulthood have not been systematically elucidated. In this study, both 10 and 15 mg/kg MAM-exposed mice exhibited schizophrenia-related phenotypes in both adolescence and adulthood, including spontaneous locomotion hyperactivity and deficits in prepulse inhibition. We observed that there was an obvious parvalbumin (PV) loss in the mPFC and hippocampus of MAM-exposed mice, extending from adolescence to adulthood. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons at mPFC and hippocampus was significantly dampened in the 10 and 15 mg/kg MAM-exposed mice. Furthermore, the firing rate of putative pyramidal neurons in mPFC and hippocampus was increased, while that of putative inhibitory neurons was decreased during both adolescence and adulthood. In conclusion, PV loss in mPFC and hippocampus of MAM-exposed mice may contribute to the impaired inhibitory function leading to the attenuation of inhibition in the brain both in vitro and in vivo., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 He et al.)

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current ( I h ). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels are largely unknown. In this study, we systematically compared the modulation of I h by synaptic potentiation in hippocampal CA1 pyramidal neurons and stratum radiatum (sRad) interneurons in mouse organotypic cultures. I h properties were similar in inhibitory and excitatory neurons and contributed to resting membrane potential and action potential firing. We found that in sRad interneurons, HCN channels were downregulated after synaptic plasticity, irrespective of the strength of synaptic potentiation. This suggests differential regulation of I h in excitatory and inhibitory neurons, possibly signifying their distinct role in network activity., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Herstel and Wierenga.)

Active dendritic integrative mechanisms such as regenerative dendritic spikes enrich the information processing abilities of neurons and fundamentally contribute to behaviorally relevant computations. Dendritic Ca 2+ spikes are generally thought to produce plateau-like dendritic depolarization and somatic complex spike burst (CSB) firing, which can initiate rapid changes in spatial coding properties of hippocampal pyramidal cells (PCs). However, here we reveal that a morpho-topographically distinguishable subpopulation of rat and mouse hippocampal CA3PCs exhibits compound apical dendritic Ca 2+ spikes with unusually short duration that do not support the firing of sustained CSBs. These Ca 2+ spikes are mediated by L-type Ca 2+ channels and their time course is restricted by A- and M-type K + channels. Cholinergic activation powerfully converts short Ca 2+ spikes to long-duration forms, and facilitates and prolongs CSB firing. We propose that cholinergic neuromodulation controls the ability of a CA3PC subtype to generate sustained plateau potentials, providing a state-dependent dendritic mechanism for memory encoding and retrieval., Competing Interests: Competing interests statement:The authors declare no competing interest.

Long-term changes of synaptic transmission can be induced by Hebbian-type homosynaptic mechanisms which require activation of both pre- and postsynapse and mediate associative learning, as well as by heterosynaptic mechanisms which do not require activation of the presynapse and are non-associative. The rules for induction of homosynaptic plasticity depend on the distance of the synapse from the soma. Does induction of heterosynaptic plasticity also depend on synaptic location? Here, we investigated heterosynaptic changes in pharmacologically isolated glutamatergic inputs arriving at either the proximal or the distal segments of the apical dendrite of layer 2/3 pyramidal neurons in rat visual cortex. We show that bursts of action potentials evoked without presynaptic stimulation induced potentiation of proximal inputs while having little effect on distal inputs. Such gradient of plasticity could be related to the attenuation of backpropagating action potentials along the dendrites. Thus, the location of the synapse on the dendritic tree is a determinant not only for homosynaptic but also for heterosynaptic plasticity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexey Malyshev reports financial support was provided by Russian Science Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch-clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV→PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV→PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Sutley-Koury et al.)

Layer V neurons in primary motor cortex (M1) are required for motor skill learning. We analyzed training-induced plasticity using a whole-cell slice patch-clamp technique with a rotor rod task, and found that training induces diverse changes in intrinsic properties and synaptic plasticity in M1 layer V neurons. Although the causal relationship between specific cellular changes and motor performance is unclear, by linking individual motor performance to cellular/synaptic functions, we identified several cellular and synaptic parameters that represent acquired motor skills. With respect to cellular properties, motor performance was positively correlated with resting membrane potential and fast afterhyperpolarization, but not with the membrane resistance, capacitance, or threshold. With respect to synaptic function, the performance was positively correlated with AMPA receptor-mediated postsynaptic currents, but not with GABA A receptor-mediated postsynaptic currents. With respect to live imaging analysis in Thy1-YFP mice, we further demonstrated a cross-correlation between motor performance, spine head volume, and self-entropy per spine. In the present study, we identified several changes in M1 layer V pyramidal neurons after motor training that represent acquired motor skills. Furthermore, training increased extracellular acetylcholine levels known to promote synaptic plasticity, which is correlated with individual motor performance. These results suggest that systematic control of specific intracellular parameters and enhancement of synaptic plasticity in M1 layer V neurons may be useful for improving motor skills., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Firing rate models for describing the mean-field activities of neuronal ensembles can be used effectively to study network function and dynamics, including synchronization and rhythmicity of excitatory-inhibitory populations. However, traditional Wilson-Cowan-like models, even when extended to include an explicit dynamic synaptic activation variable, are found unable to capture some dynamics such as Interneuronal Network Gamma oscillations (ING). Use of an explicit delay is helpful in simulations at the expense of complicating mathematical analysis. We resolve this issue by introducing a dynamic variable, u, that acts as an effective delay in the negative feedback loop between firing rate (r) and synaptic gating of inhibition (s). In effect, u endows synaptic activation with second order dynamics. With linear stability analysis, numerical branch-tracking and simulations, we show that our r-u-s rate model captures some key qualitative features of spiking network models for ING. We also propose an alternative formulation, a v-u-s model, in which mean membrane potential v satisfies an averaged current-balance equation. Furthermore, we extend the framework to E-I networks. With our six-variable v-u-s model, we demonstrate in firing rate models the transition from Pyramidal-Interneuronal Network Gamma (PING) to ING by increasing the external drive to the inhibitory population without adjusting synaptic weights. Having PING and ING available in a single network, without invoking synaptic blockers, is plausible and natural for explaining the emergence and transition of two different types of gamma oscillations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The dorsal cornu ammonis 2 (dCA2) region of the hippocampus enables the discrimination of novel from familiar conspecifics. However, the neural bases for more complex social-spatial episodic memories are unknown. Here we report that the spatial and social contents of an aversive social experience require distinct hippocampal regions. While dorsal CA1 (dCA1) pyramidal neurons mediate the memory of an aversive location, dCA2 pyramidal neurons enable the discrimination of threat-associated (CS + ) from safety-associated (CS - ) conspecifics in both female and male mice. Silencing dCA2 during encoding or recall trials disrupted social fear discrimination memory, resulting in fear responses toward both the CS + and CS - mice. Calcium imaging revealed that the aversive experience strengthened and stabilized dCA2 representations of both the CS + and CS - mice, with the incorporation of an abstract representation of social valence into representations of social identity. Thus, dCA2 contributes to both social novelty detection and the adaptive discrimination of threat-associated from safety-associated individuals during an aversive social episodic experience., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: The anterior cingulate cortex (ACC) plays a crucial role in the perception of pain. It is consistently activated by noxious stimuli and its hyperactivity in chronic pain indicates plasticity in the local neuronal network. However, the way persistent pain effects and modifies different neuronal cell types in the ACC and how this contributes to sensory sensitization is not completely understood. This study confirms the existence of 2 primary subtypes of pyramidal neurons in layer 5 of the rostral, agranular ACC, which we could classify as intratelencephalic (IT) and cortico-subcortical (SC) projecting neurons, similar to other cortical brain areas. Through retrograde labeling, whole-cell patch-clamp recording, and morphological analysis, we thoroughly characterized their different electrophysiological and morphological properties. When examining the effects of peripheral inflammatory pain on these neuronal subtypes, we observed time-dependent plastic changes in excitability. During the acute phase, both subtypes exhibited reduced excitability, which normalized to pre-inflammatory levels after day 7. Daily conditioning with nociceptive stimuli during this period induced an increase in excitability specifically in SC neurons, which was correlated with a decrease in mechanical sensitization. Subsequent inhibition of the activity of SC neurons projecting to the periaqueductal gray with in vivo chemogenetics, resulted in reinstatement of the hypersensitivity. Accordingly, it was sufficient to enhance the excitability of these neurons chemogenetically in the inflammatory pain condition to induce hypoalgesia. These findings suggest a cell type-specific effect on the descending control of nociception and a cellular mechanism for pain-induced analgesia. Furthermore, increased excitability in this neuronal population is hypoalgesic rather than hyperalgesic., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The primate dorsolateral prefrontal cortex (DLPFC) displays unique in vivo activity patterns, but how in vivo activity regulates DLPFC pyramidal neuron (PN) properties remains unclear. We assessed the effects of in vivo Kir2.1 overexpression, a genetic silencing tool, on synapses in monkey DLPFC PNs. We show for the first time that recombinant ion channel expression successfully modifies the excitability of primate cortex neurons, producing effects on synaptic properties apparently different from those in the rodent cortex.

Transcranial direct current stimulation (tDCS) is an important method for treating mental illnesses and neurodegenerative diseases. This paper reconstructed two ex vivo brain slice models based on rat brain slice staining images and magnetic resonance imaging (MRI) data respectively, and the current densities of hippocampus after cortical tDCS were obtained through finite element calculation. Subsequently, a neuron model was used to calculate the response of rat hippocampal pyramidal neuron under these current densities, and the neuronal responses of the two models under different stimulation parameters were compared. The results show that a minimum stimulation voltage of 17 V can excite hippocampal pyramidal neuron in the model based on brain slice staining images, while 24 V is required in the MRI-based model. The results indicate that the model based on brain slice staining images has advantages in precision and electric field propagation simulation, and its results are closer to real measurements, which can provide guidance for the selection of tDCS parameters and scientific basis for precise stimulation.

γ-Aminobutyric acid (GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA A receptor positive allosteric modulators are emerging as promising in clinical practice, their precise antidepressant mechanism remains to be further elucidated. The aim of the present study was to investigate the effects of LY-02, a novel compound derived from the metabolite of timosaponin, on depression in animals and its mechanism. The results of behavioral tests showed that LY-02 exhibited better antidepressant effects in both male C57BL/6 mice and Sprague Dawley (SD) rats. The results of cellular voltage clamp experiments showed that LY-02 enhanced GABA-mediated currents in HEK293T cells expressing recombinant α6β3δ subunit-containing GABA A receptors. Electrophysiological recording from brain slices showed that LY-02 decreased the amplitude of spontaneous inhibitory postsynaptic current (sIPSC) and increased action potentials of pyramidal neurons in the medial prefrontal cortex (mPFC) of C57BL/6 mice. Western blot results showed that LY-02 dose-dependently up-regulated the protein expression levels of brain-derived neurotrophic factor (BDNF), tropomyosin related kinase B (TrkB) and postsynaptic density protein 95 (PSD-95) in mPFC of mice. The above results suggest that LY-02, as a positive modulator of GABA A receptors, reduces inhibitory neurotransmission in pyramidal neurons. It further activates the BDNF/TrkB signaling pathway, thus exerting antidepressant effects. It suggests that LY-02 is a potential novel therapeutic agent for depression treatment.

Capacitance of biological membranes is determined by the properties of the lipid portion of the membrane as well as the morphological features of a cell. In neurons, membrane capacitance is a determining factor of synaptic integration, action potential propagation speed, and firing frequency due to its direct effect on the membrane time constant. Besides slow changes associated with increased morphological complexity during postnatal maturation, neuronal membrane capacitance is considered a stable, non-regulated, and constant magnitude. Here we report that, in two excitatory neuronal cell types, pyramidal cells of the mouse primary visual cortex and granule cells of the hippocampus, the membrane capacitance significantly changes between the start and the end of a daily light-dark cycle. The changes are large, nearly 2-fold in magnitude in pyramidal cells, but are not observed in cortical parvalbumin-expressing inhibitory interneurons. Consistent with daily capacitance fluctuations, the time window for synaptic integration also changes in pyramidal cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Maintenance of proper electrophysiological and connectivity profiles in the adult brain may be a perturbation point in neurodevelopmental disorders (NDDs). How these profiles are maintained within mature circuits is unclear. We recently demonstrated that postnatal ablation of the Aristaless (Arx) homeobox gene in parvalbumin interneurons (PVIs) alone led to dysregulation of their transcriptome and alterations in their functional as well as network properties in the hippocampal cornu Ammoni first region (CA1). Here, we characterized CA1 pyramidal cells (PCs) responses in this conditional knockout (CKO) mouse to further understand the circuit mechanisms by which postnatal Arx expression regulates mature CA1 circuits. Field recordings of network excitability showed that CA1 PC ensembles were less excitable in response to unpaired stimulations but exhibited enhanced excitability in response to paired-pulse stimulations. Whole-cell voltage clamp recordings revealed a significant increase in the frequency of spontaneous inhibitory postsynaptic currents onto PCs. In contrast, excitatory drive from evoked synaptic transmission was reduced while that of inhibitory synaptic transmission was increased. Current clamp recordings showed increase excitability in several sub- and threshold membrane properties that correlated with an increase in voltage-gated Na + current. Our data suggest that, in addition to cell-autonomous disruption in PVIs, loss of Arx postnatal transcriptional activity in PVIs led to complex dysfunctions in PCs in CA1 microcircuits. These non-cell autonomous effects are likely the product of breakdown in feedback and/or feedforward processes and should be considered as fundamental contributors to the circuit mechanisms of NDDs such as Arx-linked early-onset epileptic encephalopathies., 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 © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

Inhibitory interneurons are pivotal components of cortical circuits. Beyond providing inhibition, they have been proposed to coordinate the firing of excitatory neurons within cell assemblies. While the roles of specific interneuron subtypes have been extensively studied, their influence on pyramidal cell synchrony in vivo remains elusive. Employing an all-optical approach in mice, we simultaneously recorded hippocampal interneurons and pyramidal cells and probed the network influence of individual interneurons using optogenetics. We demonstrate that CA1 interneurons form a functionally interconnected network that promotes synchrony through disinhibition during awake immobility, while preserving endogenous cell assemblies. Our network model underscores the importance of both cell assemblies and dense, unspecific interneuron connectivity in explaining our experimental findings, suggesting that interneurons may operate not only via division of labor but also through concerted activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bocchio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding how genetically encoded rules drive and guide complex neuronal growth processes is essential to comprehending the brain's architecture, and agent-based models (ABMs) offer a powerful simulation approach to further develop this understanding. However, accurately calibrating these models remains a challenge. Here, we present a novel application of Approximate Bayesian Computation (ABC) to address this issue. ABMs are based on parametrized stochastic rules that describe the time evolution of small components-the so-called agents-discretizing the system, leading to stochastic simulations that require appropriate treatment. Mathematically, the calibration defines a stochastic inverse problem. We propose to address it in a Bayesian setting using ABC. We facilitate the repeated comparison between data and simulations by quantifying the morphological information of single neurons with so-called morphometrics and resort to statistical distances to measure discrepancies between populations thereof. We conduct experiments on synthetic as well as experimental data. We find that ABC utilizing Sequential Monte Carlo sampling and the Wasserstein distance finds accurate posterior parameter distributions for representative ABMs. We further demonstrate that these ABMs capture specific features of pyramidal cells of the hippocampus (CA1). Overall, this work establishes a robust framework for calibrating agent-based neuronal growth models and opens the door for future investigations using Bayesian techniques for model building, verification, and adequacy assessment., (© 2024. The Author(s).)

Sensory stimulations at 40 Hz gamma (but not any other frequency), have shown promise in reversing Alzheimer's disease (AD)-related pathologies. What distinguishes 40 Hz? We hypothesized that stimuli at 40 Hz might summate more efficiently (temporal summation) or propagate more efficiently between cortical layers (vertically), or along cortical laminas (horizontally), compared to inputs at 20 or 83 Hz. To investigate these hypotheses, we used brain slices from AD mouse model animals (5xFAD). Extracellular (synaptic) stimuli were delivered in cortical layer 4 (L4). Leveraging a fluorescent voltage indicator (VSFP) expressed in cortical pyramidal neurons, we simultaneously monitored evoked cortical depolarizations at multiple sites, at 1 kHz sampling frequency. Experimental groups (AD-Female, CTRL-Female, AD-Male, and CTRL-Male) were tested at three stimulation frequencies (20, 40, and 83 Hz). Despite our initial hypothesis, two parameters-temporal summation of voltage waveforms and the strength of propagation through the cortical neuropil-did not reveal any distinct advantage of 40 Hz stimulation. Significant physiological differences between AD and Control mice were found at all stimulation frequencies tested, while the 40 Hz stimulation frequency was not remarkable., (© 2024. The Author(s).)

G protein-gated inwardly rectifying K + (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters in the hippocampus and are implicated in neurological disorders characterized by cognitive deficits. Here, we show that enhancement or suppression of GIRK channel activity in dorsal CA1 pyramidal neurons disrupted novel object recognition in mice, without impacting open field activity or avoidance behavior. Contextual fear learning was also unaffected, but extinction of contextual fear was disrupted by suppression of GIRK channel activity in male mice. Thus, the strength of GIRK channel activity in dorsal CA1 pyramidal neurons regulates select cognitive task performance in mice., (© 2024 Luo et al.; Published by Cold Spring Harbor Laboratory Press.)

In calcium imaging studies, Ca 2+ transients are commonly interpreted as neuronal action potentials (APs). However, our findings demonstrate that robust optical Ca 2+ transients primarily stem from complex "AP-Plateaus", while simple APs lacking underlying depolarization envelopes produce much weaker photonic signatures. Under challenging in vivo conditions, these "AP-Plateaus" are likely to surpass noise levels, thus dominating the Ca 2+ recordings. In spontaneously active neuronal culture, optical Ca 2+ transients (OGB1-AM, GCaMP6f) exhibited approximately tenfold greater amplitude and twofold longer half-width compared to optical voltage transients (ArcLightD). The amplitude of the ArcLightD signal exhibited a strong correlation with the duration of the underlying membrane depolarization, and a weaker correlation with the presence of a fast sodium AP. Specifically, ArcLightD exhibited robust responsiveness to the slow "foot" but not the fast "trunk" of the neuronal AP. Particularly potent stimulators of optical signals in both Ca 2+ and voltage imaging modalities were APs combined with plateau potentials (AP-Plateaus), resembling dendritic Ca 2+ spikes or "UP states" in pyramidal neurons. Interestingly, even the spikeless plateaus (amplitude > 10 mV, duration > 200 ms) could generate conspicuous Ca 2+ optical signals in neurons. Therefore, in certain circumstances, Ca 2+ transients should not be interpreted solely as indicators of neuronal AP firing., (© 2024. The Author(s).)

Sensory abnormalities are observed in ~90% of individuals with autism spectrum disorders (ASD), but the underlying mechanisms are poorly understood. GluN2B, an NMDA receptor subunit that regulates long-term depression and circuit refinement during brain development, has been strongly implicated in ASD, but whether GRIN2B mutations lead to sensory abnormalities remains unclear. Here, we report that Grin2b-mutant mice show behavioral sensory hypersensitivity and brain hyperconnectivity associated with the anterior cingulate cortex (ACC). Grin2b-mutant mice with a patient-derived C456Y mutation (Grin2b C456Y/+ ) show sensory hypersensitivity to mechanical, thermal, and electrical stimuli through supraspinal mechanisms. c-fos and functional magnetic resonance imaging indicate that the ACC is hyperactive and hyperconnected with other brain regions under baseline and stimulation conditions. ACC pyramidal neurons show increased excitatory synaptic transmission. Chemogenetic inhibition of ACC pyramidal neurons normalizes ACC hyperconnectivity and sensory hypersensitivity. These results suggest that GluN2B critically regulates ASD-related cortical connectivity and sensory brain functions., (© 2024. The Author(s).)

Consciousness, defined as being aware of and responsive to one's surroundings, is characteristic of normal waking life and typically is lost during sleep and general anaesthesia. The traditional view of consciousness as a global brain state has evolved toward a more sophisticated interplay between global and local states, with the presence of local sleep in the awake brain and local wakefulness in the sleeping brain. However, this interplay is not clear for general anaesthesia, where loss of consciousness was recently suggested to be associated with a global state of brain-wide synchrony that selectively involves layer 5 cortical pyramidal neurons across sensory, motor and associative areas. According to this global view, local wakefulness of layer 5 cortex should be incompatible with deep anaesthesia, a hypothesis that deserves to be scrutinised with causal manipulations. Here, we show that unilateral chemogenetic activation of layer 5 pyramidal neurons in the sensorimotor cortex of isoflurane-anaesthetised mice induces a local state transition from slow-wave activity to tonic firing in the transfected hemisphere. This wakefulness-like activity dramatically disrupts layer 5 interhemispheric synchrony with mirror-image locations in the contralateral hemisphere, but does not reduce the level of unconsciousness under deep anaesthesia, nor in the transitions to/from anaesthesia. Global layer 5 synchrony may thus be a sufficient condition for anaesthesia-induced unconsciousness, but is not a necessary one, at least under isoflurane anaesthesia. Local wakefulness-like activity of layer 5 cortex can be induced and maintained under deep anaesthesia, encouraging further investigation into the local vs. global aspects of anaesthesia-induced unconsciousness. KEY POINTS: The neural correlates of consciousness have evolved from global brain states to a nuanced interplay between global and local states, evident in terms of local sleep in awake brains and local wakefulness in sleeping brains. The concept of local wakefulness remains unclear for general anaesthesia, where the loss of consciousness has been recently suggested to involve brain-wide synchrony of layer 5 cortical neurons. We found that local wakefulness-like activity of layer 5 cortical can be chemogenetically induced in anaesthetised mice without affecting the depth of anaesthesia or the transitions to and from unconsciousness. Global layer 5 synchrony may thus be a sufficient but not necessary feature for the unconsciousness induced by general anaesthesia. Local wakefulness-like activity of layer 5 neurons is compatible with general anaesthesia, thus promoting further investigation into the local vs. global aspects of anaesthesia-induced unconsciousness., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

The hippocampus is considered essential for several forms of declarative memory, including spatial and social memory. Despite the extensive research of the classic subfields of the hippocampus, the fasciola cinerea (FC)-a medially located structure within the hippocampal formation-has remained largely unexplored. In the present study, we performed a morpho-functional characterization of principal neurons in the mouse FC. Using in vivo juxtacellular recording of single neurons, we found that FC neurons are distinct from neighboring CA1 pyramidal cells, both morphologically and electrophysiologically. Specifically, FC neurons displayed non-pyramidal morphology and granule cell-like apical dendrites. Compared to neighboring CA1 pyramidal neurons, FC neurons exhibited more regular in vivo firing patterns and a lower tendency to fire spikes at short interspike intervals. Furthermore, tracing experiments revealed that the FC receives inputs from the lateral but not the medial entorhinal cortex and CA3, and it provides a major intra-hippocampal projection to the septal CA2 and sparser inputs to the distal CA1. Overall, our results indicate that the FC is a morphologically and electrophysiologically distinct subfield of the hippocampal formation; given the established role of CA2 in social memory and seizure initiation, the unique efferent intra-hippocampal connectivity of the FC points to possible roles in social cognition and temporal lobe epilepsy., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)