Pyramidal Neurons Research Articles

Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors

Abstract Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in the basolateral amygdala (BLA). This phenomenon coincided with increased intrinsic excitability and spontaneous synaptic activity of BLA pyramidal neurons associated with reduced small conductance calcium-activated potassium (SK) channel currents. Importantly, colonizing GF mice to live microbes or the microbial-derived metabolite indoles reverted SK channel activities in BLA pyramidal neurons and reduced the anxiety behavioral phenotype. These results are consistent with a molecular mechanism by which microbes and or microbial-derived indoles, regulate functional changes in the BLA neurons. Moreover, this microbe metabolite regulation of anxiety links these results to ancient evolutionarily conserved defense mechanisms associated with anxiety-related behaviors in mammals.

Alterations of Adult Prefrontal Circuits Induced by Early Postnatal Fluoxetine Treatment Mediated by 5-HT7 Receptors

The prefrontal cortex (PFC) plays a key role in high-level cognitive functions and emotional behaviors, and PFC alterations correlate with different brain disorders including major depression and anxiety. In mice, the first two postnatal weeks represent a critical period of high sensitivity to environmental changes. In this temporal window, serotonin (5-HT) levels regulate the wiring of PFC cortical neurons. Early-life insults and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affect PFC development leading to depressive and anxiety-like phenotypes in adult mice. However, the mechanisms responsible for these dysfunctions remain obscure. We found that early postnatal FLX exposure (PNFLX) results in reduced overall firing and high-frequency bursting of putative pyramidal neurons (PNs) of deep layers of the medial PFC of adult mice of both sexes in vivo. Ex vivo, patch-clamp recordings revealed that PNFLX abolished high-frequency firing in a distinct subpopulation of deep-layer mPFC PNs, which transiently express the serotonin transporter SERT during the first 2 postnatal weeks. SERT+ and SERT− PNs exhibit distinct morphofunctional properties. Genetic deletion of 5-HT7Rs and pharmacological 5-HT7R blockade partially rescued both the PNFLX-induced reduction of PN firing in vivo and the altered firing of SERT+ PNs in vitro. This indicates a pivotal role of this 5-HTR subtype in mediating 5-HT-dependent maturation of PFC circuits that are susceptible to early-life insults. Overall, our results suggest potential novel neurobiological mechanisms, underlying detrimental neurodevelopmental consequences induced by early-life alterations of 5-HT levels.

Dendritic excitations govern back-propagation via a spike-rate accelerometer.

Dendrites on neurons support electrical excitations, but the computational significance of these events is not well understood. We developed molecular, optical, and computational tools for all-optical electrophysiology in dendrites. We mapped sub-millisecond voltage dynamics throughout the dendritic trees of CA1 pyramidal neurons under diverse optogenetic and synaptic stimulus patterns, in acute brain slices. Our data show history-dependent spike back-propagation in distal dendrites, driven by locally generated Na+ spikes (dSpikes). Dendritic depolarization created a transient window for dSpike propagation, opened by A-type KV channel inactivation, and closed by slow NaV inactivation. Collisions of dSpikes with synaptic inputs triggered calcium channel and N-methyl-D-aspartate receptor (NMDAR)-dependent dendritic plateau potentials and accompanying complex spikes at the soma. This hierarchical ion channel network acts as a spike-rate accelerometer, providing an intuitive picture connecting dendritic biophysics to associative plasticity rules.

Translaminar synchronous neuronal activity is required for columnar synaptic strengthening in the mouse neocortex

Synchronous neuronal activity is a hallmark of the developing mouse primary somatosensory cortex. While the patterns of synchronous neuronal activity in cortical layer 2/3 have been well described, the source of the robust layer 2/3 activity is still unknown. Using a novel microprism preparation and in vivo 2-photon imaging in neonatal mice, we show that synchronous neuronal activity is organized in barrel columns across layers. Monosynaptic rabies tracing and slice electrophysiology experiments reveal that layer 2/3 pyramidal neurons receive significant layer 5 inputs during the first postnatal week, and silencing layer 5 synaptic outputs results in a significant reduction in spontaneous activity, abnormal sensory-evoked activity and disrupted layer 4-layer 2/3 connectivity. Our results demonstrate that translaminar layer 5-layer 2/3 connectivity plays an important role in synchronizing the developing barrel column to ensure the strengthening of layer 4-layer 2/3 connections, supporting the formation of the canonical cortical organization in barrel cortex.

Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs.

Endocytosis, required for the uptake of receptors and their ligands, can also introduce pathological aggregates such as α-synuclein (α-syn) in Parkinson's Disease. We show here the unexpected presence of intrinsically perforated endolysosomes in neurons, suggesting involvement in the genesis of toxic α-syn aggregates induced by internalized preformed fibrils (PFFs). Aggregation of endogenous α-syn in late endosomes and lysosomes of human iPSC-derived neurons (iNs), seeded by internalized α-syn PFFs, caused the death of the iNs but not of the parental iPSCs and non-neuronal cells. Live-cell imaging of iNs showed constitutive perforations in ∼5% of their endolysosomes. These perforations, identified by 3D electron microscopy in iNs and CA1 pyramidal neurons and absent in non-neuronal cells, may facilitate cytosolic access of endogenous α-syn to PFFs in the lumen of endolysosomes, triggering aggregation. Inhibiting the PIKfyve phosphoinositol kinase reduced α-syn aggregation and associated iN death, even with ongoing PFF endolysosomal entry, suggesting that maintaining endolysosomal integrity might afford a therapeutic strategy to counteract synucleinopathies.

UBE3A controls axon initial segment in the cortical pyramidal neurons

UBE3A controls axon initial segment in the cortical pyramidal neurons

Oxycodone Relapse Induces Sex-Dependent Impairments in Sustained Attention and Pyramidal Neurons of the Medial Prefrontal Cortex

Oxycodone Relapse Induces Sex-Dependent Impairments in Sustained Attention and Pyramidal Neurons of the Medial Prefrontal Cortex

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia.

Prematurely born infants often experience frequent hypoxic episodes due to immaturity of respiratory control resulting in disturbances of cortical development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters maturation of cortical excitatory and inhibitory circuits that can be detected early with functional MRI. C57BL/6 mouse male and female pups were exposed to an intermittent hypoxia (IH) regimen from P3 to P7, corresponding to pre-term humans. Adult mice after neonatal IH exhibited motor hyperactivity and impaired motor learning in complex wheel tests. Patch clamp and evoked field potential recordings revealed increased glutamatergic synaptic transmission. To investigate the role of GABAergic inhibition on glutamatergic transmission during the developmental, we applied a selective GABAA receptor inhibitor picrotoxin. A decreased synaptic inhibitory drive in the motor cortex was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo with picrotoxin injection, and decreased interneuron density. There was also an increased tonic depolarizing effect of picrotoxin after IH on Betz cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase in regional homogeneity index after picrotoxin injection in the IH group.The increased glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH.Significance Statement The study demonstrates that perinatal hypoxic brain injury disrupts the balance between excitatory and inhibitory neurotransmission in developing cortical networks. This disruption, potentially caused by functional deficiencies in GABAergic interneurons alongside increased glutamatergic transmission, may contribute to altered brain connectivity and the observed behavioral deficits, including hyperactivity and cognitive difficulties. This research provides insights into how perinatal brain injury disrupts the balance of neural excitation and inhibition, which can be detected as altered local resting-state fMRI connectivity. These findings contribute to our understanding of possible cellular underpinning of clinical fMRI findings after perinatal brain injury.

Dynamic changes of excitatory and inhibitory synapses in layer II/III of the primary motor cortex after peripheral nerve repair.

Peripheral nerve injury disrupts communication between the primary motor cortex (M1) and the target muscle, leading to alterations in synaptic plasticity within the lesion projection zone (LPZ). While nerve repair holds the potential to restore this pathway and further modulate synaptic plasticity within the LPZ, the underlying mechanisms remain incompletely understood. In this study, we established a rat model with immediate repair following unilateral median nerve transection and categorized the functional recovery of the affected limb into three phases: the injury phase, recovery phase, and rehabilitation phase, corresponding to stages of muscle non-reinnervation, gradual reinnervation, and completed reinnervation, respectively. Our findings revealed that during these phases, excitatory synaptic transmission in M1 layer II/III pyramidal neurons initially decreases, then increases, and ultimately returns to baseline levels. Conversely, inhibitory synaptic transmission initially increases, then decreases, and remains reduced even after full peripheral recovery, accompanied by upregulation of inhibitory synaptic receptors. These findings suggest that excitatory and inhibitory synaptic plasticity play opposing roles in the nerve repair process, with excitatory plasticity primarily involved in short-term responses and inhibitory plasticity contributing to both short-term and long-term modulation.

Supralinear dendritic integration in murine dendrite-targeting interneurons.

Non-linear summation of synaptic inputs to the dendrites of pyramidal neurons has been proposed to increase the computation capacity of neurons through coincidence detection, signal amplification, and additional logic operations such as XOR. Supralinear dendritic integration has been documented extensively in principal neurons, mediated by several voltage-dependent conductances. It has also been reported in parvalbumin-positive hippocampal basket cells, in dendrites innervated by feedback excitatory synapses. Whether other interneurons, which support feed-forward or feedback inhibition of principal neuron dendrites, also exhibit local non-linear integration of synaptic excitation is not known. Here, we use patch-clamp electrophysiology, and two-photon calcium imaging and glutamate uncaging, to show that supralinear dendritic integration of near-synchronous spatially clustered glutamate-receptor mediated depolarization occurs in NDNF-positive neurogliaform cells and oriens-lacunosum moleculare interneurons in the mouse hippocampus. Supralinear summation was detected via recordings of somatic depolarizations elicited by uncaging of glutamate on dendritic fragments, and, in neurogliaform cells, by concurrent imaging of dendritic calcium transients. Supralinearity was abolished by blocking NMDA receptors (NMDARs) but resisted blockade of voltage-gated sodium channels. Blocking L-type calcium channels abolished supralinear calcium signalling but only had a minor effect on voltage supralinearity. Dendritic boosting of spatially clustered synaptic signals argues for previously unappreciated computational complexity in dendrite-projecting inhibitory cells of the hippocampus.

Synchronicity of pyramidal neurones in the neocortex dominates isoflurane-induced burst suppression in mice.

Anaesthesia-induced burst suppression signifies profound cerebral inactivation. Although considerable efforts have been directed towards elucidating the electroencephalographic manifestation of burst suppression, the neuronal underpinnings that give rise to isoflurane-induced burst suppression are unclear. Electroencephalography combined with micro-endoscopic calcium imaging was used to investigate the neural mechanisms of isoflurane-induced burst suppression. Synchronous activities of pyramidal neurones in the auditory cortex and medial prefrontal cortex and inhibitory neurones in the auditory cortex (including parvalbumin [PV], somatostatin [SST], and vasoactive intestinal peptide [Vip]) and subcortical regions (including the medial geniculate body, locus coeruleus, and thalamic reticular nucleus) were recorded during isoflurane anaesthesia. In addition, the effects of chemogenetic manipulation inhibitory neurones in the auditory cortex on isoflurane-induced burst suppression were studied. Isoflurane-induced burst suppression was highly correlated with the synchronous activities of excitatory neurones in the cortex (∼65% positively and ∼20% negatively correlated neurones). Conversely, a minimal or absent correlation was observed with the neuronal synchrony of inhibitory interneurones and with neuronal activities within subcortical areas. Only activation or inhibition of PV neurones, but not SST or Vip neurones, decreased (P<0.0001) or increased (P<0.0001) isoflurane-induced neuronal synchrony. Isoflurane-induced burst suppression might be primarily driven by the synchronous activities of excitatory pyramidal neurones in the cortex, which could be bidirectionally regulated by manipulating the activity of inhibitory PV interneurones. Our findings provide new insights into the neuronal mechanisms underlying burst suppression.

Downmodulation of potassium conductances induces epileptic seizures in cortical network models via multiple synergistic factors.

Voltage-gated potassium conductances [Formula: see text] play a critical role not only in normal neural function, but also in many neurological disorders and related therapeutic interventions. In particular, in an important animal model of epileptic seizures, 4-aminopyridine (4-AP) administration is thought to induce seizures by reducing [Formula: see text] in cortex and other brain areas. Interestingly, 4-AP has also been useful in the treatment of neurological disorders such as multiple sclerosis (MS) and spinal cord injury, where it is thought to improve action potential propagation in axonal fibers. Here, we examined [Formula: see text] downmodulation in bio-physical models of cortical networks that included different neuron types organized in layers, potassium diffusion in interstitial and larger extracellular spaces, and glial buffering. Our findings are fourfold. First, [Formula: see text] downmodulation in pyramidal and fast-spiking inhibitory interneurons led to differential effects, making the latter much more likely to enter depolarization block. Second, both neuron types showed an increase in the duration and amplitude of action potentials, with more pronounced effects in pyramidal neurons. Third, a sufficiently strong [Formula: see text] reduction dramatically increased network synchrony, resulting in seizure like dynamics. Fourth, we hypothesized that broader action potentials were likely to not only improve their propagation, as in 4-AP therapeutic uses, but also to increase synaptic coupling. Notably, graded synapses incorporating this effect further amplified network synchronization and seizure-like dynamics. Overall, our findings elucidate different effects that [Formula: see text] downmodulation may have in cortical networks, explaining its potential role in both pathological neural dynamics and therapeutic applications.Significance Statement The modulation of voltage-gated potassium-conductances [Formula: see text] is thought to play an important role in epileptic seizures and therapeutic interventions in epilepsy, multiple sclerosis and spinal-cord injury. We show that [Formula: see text] downmodulation can lead to a cascade of effects including changes in basal excitability, broadening of action potentials resulting in enhanced robustness to synaptic noise perturbations and strengthening of synaptic coupling; and differential effects in excitatory and fast-spiking inhibitory interneurons, promoting depolarization block in the latter under high downmodulation. All these effects synergistically contribute to the emergence of seizure-like dynamics in the form of almost-periodic synchronized neuronal-population spiking in cortical networks. Under appropriate levels, [Formula: see text] downmodula tion can also have therapeutic effects by improving neuronal communication via the broadening of action potentials.

KV1 channels enable myelinated axons to transmit spikes reliably without spiking ectopically.

Action potentials (spikes) are regenerated at each node of Ranvier during saltatory transmission along a myelinated axon. The high density of voltage-gated sodium channels required by nodes to reliably transmit spikes increases the risk of ectopic spike generation in the axon. Here we show that ectopic spiking is avoided because KV1 channels prevent nodes from responding to slow depolarization; instead, axons respond selectively to rapid depolarization because KV1 channels implement a high-pass filter. To characterize this filter, we compared spike initiation properties in the soma and axon of CA1 pyramidal neurons from mice of both sexes, using spatially restricted photoactivation of channelrhodopsin-2 (ChR2) to evoke spikes in either region while simultaneously recording at the soma. Somatic photostimulation evoked repetitive spiking whereas axonal photostimulation evoked transient spiking. Blocking KV1 channels converted the axon photostimulation response to repetitive spiking and encouraged spontaneous ectopic spike initiation in the axon. According to computational modeling, the high-pass filter implemented by KV1 channels matches the axial current waveform associated with saltatory conduction, enabling axons to faithfully transmit digital signals by maximizing their signal-to-noise ratio for this task. Specifically, a node generates a single spike only when rapidly depolarized, which is precisely what occurs during saltatory conduction when a pulse of axial current (triggered by a spike occurring at the upstream node) reaches the next node. The soma and axon use distinct spike initiation mechanisms (filters) appropriate for the task required of each region, namely analog-to-digital transduction in the soma vs. digital signal transmission in the axon.Significance statement Neurons use action potentials, or spikes, to transmit information reliably over long distances. Spikes can be initiated through different dynamical mechanisms depending on the types of ion channels involved. The input required to evoke spikes differs depending on spike initiation dynamics. Using targeted optogenetic stimulation to evoke spikes in different subcellular compartments, we show that the soma and axon of pyramidal neurons use distinct spike initiation mechanisms suited to the distinct role of each compartment. Specifically, the soma uses a low-pass filter supporting analog-to-digital transduction whereas the axon uses KV1 channels to implement a high-pass filter seemingly optimized for transmitting spikes. Importantly, the high-pass filter prevents the axon from generating ectopic spikes if slowly depolarized.

The Critical Role of Self-Inhibition in Epileptic Seizures Based on Dynamic Analysis of the Corticothalamic Model

Studies have shown that inhibitory interneurons include inhibitory interneurons on fast time scales (I1) and inhibitory interneurons on slow time scales (I2), both of which can modulate epileptic activities. Based on this, we improve the corticothalamic model by introducing self-inhibition of I1 and I2 to explore the onset and transitions of epileptic activities from the dynamic perspective. First, we investigate the case that the excitatory loop between the excitatory pyramidal neurons (PY) and the thalamic relay neurons (TC) induces epileptic activities in the absence of self-inhibition. The emergence of multistability drives the system to produce a variety of epileptic activities, such as [Formula: see text]-spike-wave discharges, tonic and clonic oscillations. Subsequently, we introduce self-inhibition of inhibitory interneurons and find that the advancement or disappearance of the Hopf bifurcation leads to a reduction in the area of epileptic discharges. Finally, we explore epileptic activities induced by the self-inhibition of I1 and the excitability of TC on I1. The strong self-inhibition can effectively modulate seizures, but excessive exchange of information between TC and I1 induces absence seizures. In addition, the paper focuses on revealing the loop mechanisms and related bifurcation characteristics in various situations. Besides Hopf and fold limit cycle bifurcations, period-doubling and homoclinic bifurcations are also key factors leading to the state transitions. These may provide some theoretical guidance for the generation and evolution of seizures.

Sub-cellular population imaging tools reveal stable apical dendrites in hippocampal area CA3

Apical and basal dendrites of pyramidal neurons receive anatomically and functionally distinct inputs, implying compartment-level functional diversity during behavior. To test this, we imaged in vivo calcium signals from soma, apical dendrites, and basal dendrites in mouse hippocampal CA3 pyramidal neurons during head-fixed navigation. To capture compartment-specific population dynamics, we developed computational tools to automatically segment dendrites and extract accurate fluorescence traces from densely labeled neurons. We validated the method on sparsely labeled preparations and synthetic data, predicting an optimal labeling density for high experimental throughput and analytical accuracy. Our method detected rapid, local dendritic activity. Dendrites showed robust spatial tuning, similar to soma but with higher activity rates. Across days, apical dendrites remained more stable and outperformed in decoding of the animal’s position. Thus, population-level apical and basal dendritic differences may reflect distinct compartment-specific input-output functions and computations in CA3. These tools will facilitate future studies mapping sub-cellular activity and their relation to behavior.

Prepubertal phthalate exposure can cause histopathological alterations, DNA methylation and histone acetylation changes in rat brain.

Di-2-(ethylhexyl)phthalate (DEHP) is a phthalate derivative used extensively in a wide range of materials, such as medical devices, toys, cosmetics, and personal care products. Many mechanisms, including epigenetics, may be involved in the effects of phthalates on brain development. In this study, Sprague-Dawley male rats were obtained 21-23days after their birth (post-weaning) and were exposed to DEHP during the prepubertal period with low-dose DEHP (DEHP-L, 30mg/kg/day) and high-dose DEHP (DEHP-H, 60mg/kg/day, 37days) until the end of adolescence (PND 60). The rats in the study groups were sacrificed during adulthood, and histopathological changes, epigenetic changes, and oxidative stress parameters were evaluated in brain tissues. Histopathological findings indicating the presence of deterioration in brain tissue morphology were obtained, more prominently in the DEHP-H group. Examining the hippocampus under the light microscope, pyramidal neuron loss was detected only in CA1 of the DEHP-L group, while in DEHP-H rats, pyramidal neuron losses were detected in the CA1, CA2, and CA3 regions. No significant change was observed in brain lipid peroxidation levels with DEHP compared to control. Significant increases in total glutathione (GSH) in both dose groups were considered to be an adaptive response to DEHP-induced oxidative stress. The decrease in DNA methylation in the brain, although not statistically significant, and the increase in histone modification showed that exposure to DEHP may cause epigenetic changes in the brain and these epigenetic changes may also take place as one of the mechanisms underlying the damage observed in the brain. The results suggest that DEHP exposure during early development may have a significant effect on brain development.

Somatostatin-expressing neurons in the medial prefrontal cortex promote sevoflurane anesthesia in mice.

The medial prefrontal cortex plays a crucial role in regulating consciousness. However, the specific functions of its excitatory and inhibitory networks during anesthesia remain uncertain. Here we explored the hypothesis that somatostatin interneurons in the medial prefrontal cortex enhance the effects of sevoflurane anesthesia by increasing GABA transmission to pyramidal neurons. EEG was utilized to reflect the depth of anesthesia. Immunostaining and fiber photometry were employed to assess neuronal activities and GABA delivery. The regulation of neuronal activity was achieved by chemogenetics and optogenetics. The expression of c-Fos was increased in somatostatin neurons of the medial prefrontal cortex during sevoflurane anesthesia (air versus sevoflurane: 26.4 ± 6.5 % versus 48 ± 6.2 %, P=0.0007, n=5 mice). Chemogenetic inhibition or activation of somatostatin neurons in the medial prefrontal cortex reduced (from 84 ± 24 s to 51 ± 18 s, P=0.008, n=7 mice) or prolonged (from 97 ± 31 s to 140 ± 30 s, P=0.006, n=7 mice) the sevoflurane anesthesia recovery time. Increased GABA input to pyramidal neurons in the medial prefrontal cortex precedes sevoflurane-induced loss of consciousness (ΔF/F: from 0.46 ± 0.57 % to 2.25 ± 1.42 %, P=0.031, n=10 mice). Activation of somatostatin neurons in the medial prefrontal cortex, leading to a significant reduction in calcium signals within local pyramidal neurons (ΔF/F: from -0.14 ± 0.52 % to -10.08 ± 4.44 %, P=0.002, n=10 mice), and GABA input on pyramidal neurons increased (ΔF/F: from -0.001 ± 0.001 % to 0.28 ± 0.03 %, P=0.002, n=7 mice) in a time-locked manner. Chemogenetic inhibition of pyramidal neurons prolonged the recovery from sevoflurane anesthesia in mice (from 101 ± 46 s to 136 ± 54 s, P=0.017, n=19 mice). Cortical somatostatin neurons may inhibit local pyramidal neurons by enhancing GABA transmission, which increases the effectiveness of sevoflurane anesthesia.

The influence of high-fat diet on nicotine vapor self-administration, neuronal excitability, and leptin levels in adult mice.

With the rise in fast-food culture and the continued high numbers of tobacco-related deaths, there has been a great deal of interest in understanding the relationship between high-fat diet (HFD) and nicotine use behaviors. Using adult mice and a patch-clamp electrophysiology assay, we investigated the influence of HFD on the excitability of ventral tegmental area (VTA) dopamine neurons and pyramidal neurons in the medial prefrontal cortex (mPFC) given their role in modulating the reinforcing effects of nicotine and natural rewards. We then examined whether HFD-induced changes in peripheral markers were associated with nicotine use behaviors. Here, mice were assigned standard diet (SD) or HFD for 6 weeks and then trained to self-administer nicotine using an e-vape® self-administration (EVSA) assay. After the last session, changes in glucose, insulin, and leptin were assessed with ELISA. HFD-assigned mice displayed a decrease in intrinsic excitability of VTA dopamine neurons; but an increase in intrinsic excitability of layer VI prelimbic mPFC neurons. SD-assigned female mice demonstrated enhanced nicotine EVSA during fixed-ratio 3 relative to SD males. HFD-assigned male and female mice displayed increased nicotine EVSA during FR1. However, only HFD-assigned male mice exhibited enhanced nicotine EVSA during FR3. Finally, HFD-assigned male and female mice displayed increased leptin levels. However, we only observed a direct correlation between leptin levels and EVSA responding during FR1 in HFD-fed male mice. These results suggest that high-fat diet alter nicotine intake in a sex-specific manner, and this may be due to diet-induced changes in neuronal excitability and circulating leptin levels.

Toxicological Impacts of Pendimethalin on the Brain of Cyprinus carpio: A Histopathological Approach

Agricultural pesticides negatively impact aquatic ecosystems. A dinitroaniline herbicide pendimethalin is used to control weeds and unwanted grasses in crop fields but it can reach water streams indirectly and harm aquatic fauna including fish. The main objective of our study was to find histopathological alterations caused by pendimethalin in the brain of Cyprinus carpio. The whole procedure was done using a histopathological approach by processing brain tissue, making slides, and analyzing these slides under a light microscope to observe changes in brain tissue. Acute toxicity was found by obtaining 96h LC50 value i.e., 2.20μl/L. Fishes were divided into 3 groups: The first group was assigned as the control group., second and third groups was administered with 1/10th and 1/15th concentration of calculated 96 h LC50 (I.e., 0.22μl/L and .146μl/L). The key findings of our study demonstrated that control fish brains do not show any morphological changes in structure. The second and third groups exposed to pendimethalin showed severe damage to the brain including vacuolization, necrosis in neurons, deformed pyramidal cells, clustering of nuclei, binucleate formation and nuclear infiltration compared to the control fish brain. The findings of our study have significant implications for understanding the neurotoxic effects of pendimethalin on aquatic species, specifically about brain structure and function. The study emphasizes the crucial role of neurotoxicity assessments in environmental risk assessments, which can save particular species and preserve the general equilibrium and resilience of aquatic habitats.

Cell-type-specific networks during hippocampal seizures at the micro- and macroscale.

Epilepsy is a network disorder, involving neural circuits at both the micro- and macroscale. While local excitatory-inhibitory imbalances are recognized as a hallmark at the microscale, the dynamic role of distinct neuron types during seizures remain poorly understood. At the macroscale, interactions between key nodes within the epileptic network, such as the central median thalamic nucleus (CMT), are critical to the, hippocampal epileptic process. However, precise mechanisms underlying these interactions remain unclear. In this study, we investigated the microcircuit dynamics within the seizure onset zone and secondary spreading regions, as well as the network connectivity between the hippocampus and the CMT, using a 4-aminopyridine (4-AP) induced hippocampal seizure model. Rats were allocated into three experimental groups. The first group used a 3D tetrode array to monitor hippocampal seizure activity and microcircuit dynamics, including seizure propagation across the macroscale network. In the second group, a chemical lesion was induced in the CMT to assess its impact on hippocampal seizures. In the third group, chemogenetic techniques were used to selectively suppress pyramidal neurons in the CMT and observe changes in neural network connectivity between the CMT and hippocampus during seizures. Offline single-unit sorting was performed using KlustaKwik and further analysis was conducted with CellExplorer. At seizure onset, the narrow interneurons exhibited increased firing rates, initiating recruitment of other neurons, followed by increased activity in pyramidal neuron. Wide interneurons also showed heightened activity subsequent to pyramidal neurons. Interneurons played a more prominent role in the microcircuit during seizures compared to baseline. The CMT exhibited characteristic seizure activity and a decrease in narrow interneuron activity, whereas the cortex did not display seizure activity during hippocampal seizures. Lesioning the CMT resulted in the loss of the tonic component of hippocampal seizures and reduced overall neuronal activity in the hippocampal. Selective suppression of CMT pyramidal neurons resulted in shortened hippocampal seizures while preserving the tonic component. Narrow interneuron activity remained unchanged, while pyramidal neuron and wide interneuron activity significantly decreased. Our findings underscore the critical role of interneurons in the micronetwork of the seizure onset zone and secondary spreading region. Narrow interneurons were particularly vital in seizure initiation, whereas wide interneurons may contribute to seizure termination within the onset zone but not in the secondary spreading region. Pyramidal neurons in the CMT influence hippocampal seizures by modulating of both hippocampal pyramidal neurons and wide interneurons.