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Nature Jun 2024Memories benefit from sleep, and the reactivation and replay of waking experiences during hippocampal sharp-wave ripples (SWRs) are considered to be crucial for this...
Memories benefit from sleep, and the reactivation and replay of waking experiences during hippocampal sharp-wave ripples (SWRs) are considered to be crucial for this process. However, little is known about how these patterns are impacted by sleep loss. Here we recorded CA1 neuronal activity over 12 h in rats across maze exploration, sleep and sleep deprivation, followed by recovery sleep. We found that SWRs showed sustained or higher rates during sleep deprivation but with lower power and higher frequency ripples. Pyramidal cells exhibited sustained firing during sleep deprivation and reduced firing during sleep, yet their firing rates were comparable during SWRs regardless of sleep state. Despite the robust firing and abundance of SWRs during sleep deprivation, we found that the reactivation and replay of neuronal firing patterns was diminished during these periods and, in some cases, completely abolished compared to ad libitum sleep. Reactivation partially rebounded after recovery sleep but failed to reach the levels found in natural sleep. These results delineate the adverse consequences of sleep loss on hippocampal function at the network level and reveal a dissociation between the many SWRs elicited during sleep deprivation and the few reactivations and replays that occur during these events.
Topics: Animals; Female; Male; Rats; CA1 Region, Hippocampal; Maze Learning; Memory; Pyramidal Cells; Rats, Long-Evans; Sleep Deprivation; Sleep, Slow-Wave; Wakefulness; Time Factors; Hippocampus
PubMed: 38867049
DOI: 10.1038/s41586-024-07538-2 -
Brain Research Bulletin Aug 2024The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly...
The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly understood. In this study, we investigated the role of layer V pyramidal neurons in a mouse model of MDD induced by repeated lipopolysaccharide (LPS) administration. Our results demonstrate that three days of systemic LPS administration induced depressive-like behavior and upregulated mRNA levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β (TGF-β) in the IL cortex. Electrophysiological recordings revealed a significant decrease in the intrinsic excitability of layer V pyramidal neurons in the IL following systemic LPS exposure. Importantly, chemogenetic activation of IL pyramidal neurons ameliorated LPS-induced depressive-like behavior. Additionally, LPS administration significantly increased microglial activity in the IL, as evidenced by a greater number of Ionized calcium binding adaptor molecule-1 (IBA-1)-positive cells. Morphometric analysis further unveiled enlarged soma, decreased branch numbers, and shorter branch lengths of microglial cells in the IL cortex following LPS exposure. Moreover, the activation of pyramidal neurons by clozapine-N-oxide increased the microglia branch length but did not change branch number or cytosolic area. These results collectively suggest that targeted activation of pyramidal neurons in the IL cortex mitigates microglial response and ameliorates depressive-like behaviors induced by systemic LPS administration. Therefore, our findings offer potential therapeutic targets for the development of interventions aimed at alleviating depressive symptoms by modulating IL cortical circuitry and microglial activity.
Topics: Animals; Pyramidal Cells; Lipopolysaccharides; Mice; Male; Microglia; Mice, Inbred C57BL; Depression; Clozapine; Disease Models, Animal; Depressive Disorder, Major
PubMed: 38866373
DOI: 10.1016/j.brainresbull.2024.111008 -
Journal of Neurophysiology Jun 2024Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of...
Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTD). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole-cell patch-clamp recording. Acute MeHg exposure (20 μM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both EPSC and IPSC charge were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPAR- nor NMDAR-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.
PubMed: 38864824
DOI: 10.1152/jn.00049.2024 -
Acta Pharmacologica Sinica Jun 2024Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of...
Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca influx evoked by high K solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.
PubMed: 38862816
DOI: 10.1038/s41401-024-01275-y -
The European Journal of Neuroscience Jun 2024The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum...
The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum radiatum (SR) receives input from the hippocampal CA3 region while the distal part in the stratum-lacunosum-moleculare (SLM) receives input mainly from the entorhinal cortex. The AMPA receptor-mediated (AMPA) signalling of SLM synapses in slices from neonatal rats was previously found to considerably differ from that of the SR synapses. In the present study, AMPA signalling of SLM synapses in 1-month-old rats has been examined, that is, when the hippocampus is essentially functionally mature. For the SR synapses, this time is characterized by a facilitatory shift in short-term plasticity, in the disappearance of labile postsynaptic AMPA signalling, a property thought to be important for early activity-dependent organization of neural circuits, and the expression of an adult form of long-term potentiation. We found that the SLM synapses alter their short-term plasticity similarly to that of the SR synapses. However, the labile postsynaptic AMPA signalling was not only maintained but substantially enhanced in the SLM synapses. The long-term potentiation observed was not of the adult form but like that of the neonatal SR synapses based on unsilencing of AMPA labile synapses. We propose that these features of the SLM synapses in the mature hippocampus will help to produce a flexible map of the multimodal sensory input reaching the SLM required for its conjunctive operation with the SR input to generate a proper functional output from the CA1 region.
PubMed: 38857895
DOI: 10.1111/ejn.16440 -
Development (Cambridge, England) Jul 2024The function of medial entorhinal cortex layer II (MECII) excitatory neurons has been recently explored. MECII dysfunction underlies deficits in spatial navigation and...
The function of medial entorhinal cortex layer II (MECII) excitatory neurons has been recently explored. MECII dysfunction underlies deficits in spatial navigation and working memory. MECII neurons comprise two major excitatory neuronal populations, pyramidal island and stellate ocean cells, in addition to the inhibitory interneurons. Ocean cells express reelin and surround clusters of island cells that lack reelin expression. The influence of reelin expression by ocean cells and interneurons on their own morphological differentiation and that of MECII island cells has remained unknown. To address this, we used a conditional reelin knockout (RelncKO) mouse to induce reelin deficiency postnatally in vitro and in vivo. Reelin deficiency caused dendritic hypertrophy of ocean cells, interneurons and only proximal dendritic compartments of island cells. Ca2+ recording showed that both cell types exhibited an elevation of calcium frequencies in RelncKO, indicating that the hypertrophic effect is related to excessive Ca2+ signalling. Moreover, pharmacological receptor blockade in RelncKO mouse revealed malfunctioning of GABAB, NMDA and AMPA receptors. Collectively, this study emphasizes the significance of reelin in neuronal growth, and its absence results in dendrite hypertrophy of MECII neurons.
Topics: Reelin Protein; Animals; Entorhinal Cortex; Dendrites; Cell Adhesion Molecules, Neuronal; Serine Endopeptidases; Nerve Tissue Proteins; Extracellular Matrix Proteins; Mice, Knockout; Mice; Interneurons; Neurons; Calcium Signaling
PubMed: 38856043
DOI: 10.1242/dev.202449 -
Philosophical Transactions of the Royal... Jul 2024Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational... (Review)
Review
Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons with a specific focus on the latest developments from studies. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Pyramidal Cells; Neuronal Plasticity; Animals; Brain; Long-Term Potentiation; Synapses; Humans
PubMed: 38853566
DOI: 10.1098/rstb.2023.0231 -
Philosophical Transactions of the Royal... Jul 2024Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to...
Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Nitric Oxide; Animals; Cerebral Cortex; Presynaptic Terminals; Receptors, Kainic Acid; Patch-Clamp Techniques; Rats; Pyramidal Cells; Nitric Oxide Synthase; Mice
PubMed: 38853563
DOI: 10.1098/rstb.2023.0475 -
Philosophical Transactions of the Royal... Jul 2024Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand...
Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand better the possible impact of either LTP form, we explored a realistic model of a CA1 pyramidal cell equipped with known membrane mechanisms and multiple, stochastic excitatory axo-spinous synapses. Our simulations were designed to establish an input-output transfer function, the dependence between the frequency of presynaptic action potentials triggering probabilistic synaptic discharges and the average frequency of postsynaptic spiking. We found that, within the typical physiological range, potentiation of the postsynaptic current results in a greater overall output than an equivalent increase in presynaptic release probability. This difference grows stronger at lower input frequencies and lower release probabilities. Simulations with a non-hierarchical circular network of principal neurons indicated that equal increases in either synaptic fidelity or synaptic strength of individual connections also produce distinct changes in network activity, although the network phenomenology is likely to be complex. These observations should help to interpret the machinery of LTP phenomena documented . This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Models, Neurological; Synapses; Pyramidal Cells; Animals; Computer Simulation; Action Potentials; CA1 Region, Hippocampal
PubMed: 38853561
DOI: 10.1098/rstb.2023.0235 -
Philosophical Transactions of the Royal... Jul 2024-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic...
-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic NMDAR (pre-NMDAR) function is largely unexplored. Different pre-NMDAR subunit populations are documented at synapses, suggesting that subunit composition influences neuronal transmission. Here, we used electrophysiological recordings at Schaffer collateral-CA1 synapses partnered with Ca imaging and glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of pre-NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential-evoked Ca influx via modulation of small-conductance Ca-activated K+ channels, while activation of the GluN2A population does the opposite. Critically, the level of functional expression of the subunits is subject to homeostatic regulation, bidirectionally affecting short-term facilitation, thus providing a capacity for a fine adjustment of information transfer. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Receptors, N-Methyl-D-Aspartate; Animals; Small-Conductance Calcium-Activated Potassium Channels; Action Potentials; Calcium; Rats; Synapses; Neuronal Plasticity; Pyramidal Cells
PubMed: 38853550
DOI: 10.1098/rstb.2023.0222