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Background: Tau hyperphosphorylation at several sites, including those close to its microtubule domain (MD), is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, tau phosphorylation (pTau) at MD sites promotes neuroprotection by preventing seizure-like activity. Objective: To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (PN30-35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function. Methods: We used immunohistochemistry, T-maze, nesting test, novel object recognition test, open field arena, and electrophysiology. Results: Our results showed that the very young rTg4510 mouse model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from PN30-35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found a significant reduction in the somatic area of pTau positive pyramidal and granule neurons in the young rTg4510 mice. Despite this, improved memory and increased number of dendrites per cell in granule neurons was found. Conclusion: Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.

Neuron-microglia communication through the Cx3cr1-Cx3cl1 axis is essential for the development and refinement of neural circuits, which determine their function into adulthood. In the present work we set out to extend the behavioral characterization of Cx3cr1

The diathesis–stress model of schizophrenia posits that a constitutive factor increases the vulnerability to secondary stressors. Alterations in neuron–microglia communication through the fractalkine pathway is a potential predisposing factor. Wild-type (WT) and Cx3cr1−/− (KO) mice of both sexes randomly received either a low (0.5 mg/kg) or high dose (1 mg/kg) of MK-801 or saline during early postnatal development. Neuronal apoptosis was assessed at a midpoint of the pharmacological protocol. Survival and growth rates were determined up to adulthood when innate behaviors, unconditioned anxiety, contextual memory and seizure susceptibility were evaluated, as well as hippocampal local field potential and sensory gating. Fractalkine receptor (CX3CR1) depletion and MK-801 treatment had a synergistic effect, increasing neuronal apoptosis and overall mortality. Both factors independently induced long-lasting cognitive impairments in the wide array of tasks assessed. Low MK-801 dose treatment greatly augmented the mortality of pentylenetetrazol-induced seizures in WT mice, an effect prevented by CX3CR1 depletion. MK-801 treatment induced a shift in the power spectrum of the hippocampal local field potential towards higher frequencies that was averted in Cx3cr1−/− mice by an opposite shift. CX3CR1 depletion severely increases the vulnerability to neonatal NMDA antagonism with additional complex interactions regarding cognitive and neurophysiological effects.

Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β peptide (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility needs further exploration. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in slices. Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in slices. Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.

The main olfactory bulb (MOB) is highly plastic and constantly reconfiguring its function and structure depending on sensory experience. Despite the extensive evidence of anatomical, functional and behavioural changes in the olfactory system induced by highly variable olfactory experiences, it is still unknown whether prolonged passive odour experience could reconfigure the MOB at its input and network activity levels and whether these changes impact innate olfaction. Here, by measuring odour-induced glomerular activation, MOB network activity and innate olfactory behaviours, we described a profound MOB reconfiguration induced by prolonged passive olfactory experience in adult animals that impacts MOB input integration at the glomerular layer including an increase in the activated glomerular area and signal intensity, which is combined with a refinement in the number of activated glomeruli and less-overlapped glomerular maps. We also found that prolonged passive olfactory experience dramatically changes MOB population activity in the presence and absence of odours, which is reflected as a decrease in slow oscillations (12 Hz) and an increase in fast oscillations (12 Hz). All these functional changes in awake and anaesthetized mice correlate with an increase in brain-derived neurotrophic factor (BDNF) and with improved innate olfactory responses such as habituation/dishabituation and innate preference/avoidance. Our study shows that prolonged passive olfactory experience in adult animals produces a dramatic reconfiguration of the MOB network, possibly driven by BDNF, that improves innate olfactory responses.

Accumulation of amyloid-beta (Aβ) in temporal lobe structures, including the hippocampus, is related to a variety of Alzheimer's disease symptoms and seems to be involved in the induction of neural network hyperexcitability and even seizures. Still, a direct evaluation of the pro-epileptogenic effects of Aβ in vivo, and of the underlying mechanisms, is missing. Thus, we tested whether the intracisternal injection of Aβ modulates 4-aminopyridine (4AP)-induced epileptiform activity, hippocampal network function, and its synaptic coupling. When tested 3 weeks after its administration, Aβ (but not its vehicle) reduces the latency for 4AP-induced seizures, increases the number of generalized seizures, exacerbates the time to fully recover from seizures, and favors seizure-induced death. These pro-epileptogenic effects of Aβ correlate with a reduction in the power of the spontaneous hippocampal network activity, involving all frequency bands in vivo and only the theta band (4-10 Hz) in vitro. The pro-epileptogenic effects of Aβ also correlate with a reduction of the Schaffer-collateral CA1 synaptic coupling in vitro, which is exacerbated by the sequential bath application of 4-AP and Aβ. In summary, Aβ produces long-lasting pro-epileptic effects that can be due to alterations in the hippocampal circuit, impacting its coordinated network activity and its synaptic efficiency. It is likely that normalizing synaptic coupling and/or coordinated neural network activity (i.e., theta activity) may contribute not only to improve cognitive function in Alzheimer's disease but also to avoid hyperexcitation in conditions of amyloidosis.

Inflammation inhibits the expression of some, but not all forms of respiratory motor plasticity. For example, systemic application of lipopolysaccharide (LPS) inhibits the phrenic long-term facilitation induced by moderate-intermittent hypoxia in vivo. There are multiple pro-inflammatory processes triggered by the systemic application of LPS, including neuroinflammation in the CNS. Considering that microglia can be activated by the systemic application of LPS, it is likely that this cell type influences the response of the respiratory circuits to intermittent hypoxia (IH). Thus, we aimed to test whether modulators of microglial function would affect the response to IH of the preBotzinger complex (preBotC) isolated in a brainstem slice preparation. This experimental approach avoids the systemic influences of these microglial modulators and limits their effects on cells, mostly microglia, included in the slice. First, we found that IH (3 × 5-min episodes of bubbling with 95% N2 and 5% CO2, mixed with 5-min normoxic intervals by bubbling with 95% O2 and 5% CO2) induces a long-lasting increase in the respiratory rhythm frequency recorded directly from the preBotC, called in vitro long-term facilitation (LTF), which occurs simultaneously with a long-lasting decrease in burst amplitude. Moreover, we found that bath applications of “microglial activators” (LPS and fractalkine), “microglial inhibitors” (minocycline and fucoidan) and a microgliotoxin (liposomal clodronate) partially reduce in vitro LTF. These findings reveal a complex scenario in which both the activation and the inhibition of microglia halts IH-induced preBotC plasticity and suggest that experimental or pathological conditions that affect this cell type, almost in any way, could affect breathing and its plastic responses.

Even though the retinal microcircuit organization has been described in detail at the single-cell level, little is known about how groups of retinal cells’ coordinated activity encode and process parallel information representing the spatial and temporal structure of changing environmental conditions. To describe the population dynamics of retinal neuronal ensembles, we used microelectrode array recordings that describe hundreds of retinal ganglion cells’ simultaneous activity in response to a short movie captured in the natural environment where our subject develops their visual behaviors. The vectorization of population activity allowed the identification of retinal neuronal ensembles that synchronize to specific segments of natural stimuli. These synchronous retinal neuronal ensembles were reliably activated by the same stimuli at different trials, indicating a robust population response of retinal microcircuits. The generation of asynchronous events required integrating a physiologically meaningful time window larger than 80 ms, demonstrating that retinal neuronal ensembles’ time integration filters non-structured visual information. Interestingly, individual neurons could be part of several ensembles indicating that parallel circuits could encode environmental conditions changes. We conclude that parallel neuronal ensembles could represent the functional unit of retinal computations and propose that the further study of retinal neuronal ensembles could reveal emergent properties of retinal circuits that individual cells’ activity cannot explain.

The pre-Botzinger complex (preBotC), located within the ventral respiratory column, produces inspiratory bursts in varying degrees of synchronization/amplitude. This wide range of population burst patterns reflects the flexibility of the preBotC neurons, which is expressed in variations in the onset/offset times of their activations and their activity during the population bursts, with respiratory neurons exhibiting a large cycle-to-cycle timing jitter both at the population activity onset and at the population activity peak, suggesting that respiratory neurons are stochastically activated before and during the inspiratory bursts. However, it is still unknown whether this stochasticity is maintained while evaluating the coactivity of respiratory neuronal ensembles. Moreover, the preBotC topology also remains unknown. In this study, by simultaneously recording tens of preBotC neurons and using coactivation analysis during the inspiratory periods, we found that the preBotC has a scale-free configuration (mixture of not many highly connected nodes, hubs, with abundant poorly connected elements) exhibiting the rich-club phenomenon (hubs more likely interconnected with each other). PreBotC neurons also produce multineuronal activity patterns (MAPs) that are highly stable and change during the hypoxia-induced reconfiguration. Moreover, preBotC contains a coactivating core network shared by all its MAPs. Finally, we found a distinctive pattern of sequential coactivation of core network neurons at the beginning of the inspiratory periods, indicating that, when evaluated at the multicellular level, the coactivation of respiratory neurons seems not to be stochastic.NEW & NOTEWORTHY By means of multielectrode recordings of preBotC neurons, we evaluated their configuration in normoxia and hypoxia, finding that the preBotC exhibits a scale-free configuration with a rich-club phenomenon. preBotC neurons produce multineuronal activity patterns that are highly stable but change during hypoxia. The preBotC contains a coactivating core network that exhibit a distinctive pattern of coactivation at the beginning of inspirations. These results reveal some network basis of inspiratory rhythm generation and its reconfiguration during hypoxia.

Olfactory dysfunction is commonly observed in patients with obstructive sleep apnea (OSA), which is related to chronic intermittent hypoxia (CIH). OSA patients exhibit alterations in discrimination, identification and odor detection threshold. These olfactory functions strongly rely on neuronal processing within the main olfactory bulb (MOB). However, a direct evaluation of the effects of controlled CIH on olfaction and MOB network activity has not been performed. Here, we used electrophysiological field recordings in vivo to evaluate the effects of 21-day-long CIH on MOB network activity and its response to odors. In addition, we assessed animals´ olfaction with the buried food and habituation/dishabituation tests. We found that mice exposed to CIH show alterations in MOB spontaneous activity in vivo, consisting of a reduction in beta and gamma frequency bands power along with an increase in the theta band power. Likewise, the MOB was less responsive to odor stimulation, since the proportional increase of the power of its population activity in response to four different odorants was smaller than the one observed in control animals. These CIH-induced MOB functional alterations correlate with a reduction in the ability to detect, habituate and discriminate olfactory stimuli. Our findings indicate that CIH generates alterations in the MOB neural network, which could be involved in the olfactory deterioration in patients with OSA.

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Transgenic mice have been used to make valuable contributions to the field of neuroscience and model neurological diseases. The simultaneous functional analysis of hippocampal cell activity combined with hippocampal dependent innate task evaluations provides a reliable experimental approach to detect fine changes during early phases of neurodegeneration. To this aim, we used a merge of patch-clamp with two hippocampal innate behavior tasks. With this experimental approach, whole-cell recordings of CA1 pyramidal cells, combined with hippocampal-dependent innate behaviors, have been crucial for evaluating the early mechanism of neurodegeneration and its consequences. Here, we present our protocol for ex vivo whole-cell recordings of CA1 pyramidal cells and hippocampal dependent innate behaviors in an adolescent (p30) mice.

Perinatal inflammation triggers breathing disturbances early in life and affects the respiratory adaptations to challenging conditions, including the generation of amplitude long-term facilitation (LTF) by acute intermittent hypoxia (AIH). Some of these effects can be avoided by anti-inflammatory treatments like minocycline. Since little is known about the effects of perinatal inflammation on the inspiratory rhythm generator, located in the preBötzinger complex (preBötC), we tested the impact of acute lipopolysaccharide (LPS) systemic administration (sLPS), as well as gestational LPS (gLPS) and gestational chronic IH (gCIH), on respiratory rhythm generation and its long-term response to AIH in a brainstem slice preparation from neonatal mice. We also evaluated whether acute minocycline administration could influence these effects. We found that perinatal inflammation induced by sLPS or gLPS, as well as gCIH, modulate the frequency, signal-to-noise ratio and/or amplitude (and their regularity) of the respiratory rhythm recorded from the preBötC in the brainstem slice. Moreover, all these perinatal conditions inhibited frequency LTF and amplitude long-term depression (LTD); gCIH even induced frequency LTD of the respiratory rhythm after AIH. Some of these alterations were not observed in slices pre-treated in vitro with minocycline, when compared with slices obtained from naïve pups, suggesting that ongoing inflammatory conditions affect respiratory rhythm generation and its plasticity. Thus, it is likely that alterations in the inspiratory rhythm generator and its adaptive responses could contribute to the respiratory disturbances observed in neonates that suffered from perinatal inflammatory challenges.

Hydrogen peroxide (H2O2) is a messenger involved in both damaging neuroinflammatory responses and physiological cell communication. The ventrolateral medulla, which regulates several vital functions including breathing and blood pressure, is highly influenced by hydrogen peroxide, whose extracellular levels could be determined by hypoxia and microglial activity, both of which modulate ventrolateral medulla function. Therefore, in this study we aimed to test whether different patterns of hypoxia and/or putative microglial modulators change extracellular hydrogen peroxide in the ventrolateral medulla by using an enzymatic reactor online sensing procedure specifically designed for this purpose. With this new technique, we detected extracellular levels of hydrogen peroxide in the ventrolateral medulla in vitro, which spontaneously fluctuated. These fluctuations are reduced by minocycline, a putative microglial inhibitor, and by the microglial toxin liposomal clodronate. Suitably, lipopolysaccharide increases extracellular hydrogen peroxide, while minocycline and liposomal clodronate reduce this increase. Application of blue light to slices with microglia expressing channelrhodopsin-2 also increases extracellular hydrogen peroxide. Moreover, long-lasting and intermittent hypoxia (as well as subsequent reoxygenation) increase extracellular hydrogen peroxide to similar levels, which is partially prevented by minocycline. The effect of long-lasting hypoxia was reproduced in vivo. Overall, our data show that changes in oxygen concentration, and possibly microglial function, modulate extracellular H2O2 levels in the ventrolateral medulla, which could influence the function of this neural circuit under normal and pathological conditions related to inflammation and/or hypoxia.

Background: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. Objective: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. Method: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Results: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Conclusion: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine–treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain’s amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

Chronic intermittent hypoxia (CIH) is the most distinct feature of obstructive sleep apnea (OSA), a common breathing and sleep disorder that leads to several neuropathological consequences, including alterations in the hippocampal network and in seizure susceptibility. However, it is currently unknown whether these alterations are permanent or remit upon normal oxygenation. Here, we investigated the effects of CIH on hippocampal spontaneous network activity and hyperexcitability in vitro and explored whether these alterations endure or fade after normal oxygenation. Results showed that applying CIH for 21 days to adult rats increases gamma-band hippocampal network activity and aggravates 4-Aminopyridine-induced epileptiform activity in vitro. Interestingly, these CIH-induced alterations remit after 30 days of normal oxygenation. Our findings indicate that hippocampal network alterations and increased seizure susceptibility induced by CIH are not permanent and can be spontaneously reverted, suggesting that therapeutic interventions against OSA in patients with epilepsy, such as surgery or continuous positive airway pressure (CPAP), could be favorable for seizure control.

A variety of neurological diseases, including Alzheimer’s disease (AD), involve amyloid beta (Aβ) accumulation and/or neuroinflammation, which can alter synaptic and neural circuit functions. Consequently, these pathological conditions induce changes in neural network rhythmic activity (brain arrhythmias), which affects many brain functions. Neural network rhythms are involved in information processing, storage and retrieval, which are essential for memory consolidation, executive functioning and sensory processing. Therefore, brain arrhythmias could have catastrophic effects on circuit function, underlying the symptoms of various neurological diseases. Moreover, brain arrhythmias can serve as biomarkers for a variety of brain diseases. The aim of this review is to provide evidence linking Aβ and inflammation to neural network dysfunction, focusing on alterations in brain rhythms and their impact on cognition and sensory processing. I reviewed the most common brain arrhythmias characterized in AD, in AD transgenic models and those induced by Aβ. In addition, I reviewed the modulations of brain rhythms in neuroinflammatory diseases and those induced by immunogens, interleukins and microglia. This review reveals that Aβ and inflammation produce a complex set of effects on neural network function, which are related to the induction of brain arrhythmias and hyperexcitability, both closely related to behavioral alterations. Understanding these brain arrhythmias can help to develop therapeutic strategies to halt or prevent these neural network alterations and treat not only the arrhythmias but also the symptoms of AD and other inflammation-related pathologies.

Background: The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer's disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Methods: Immunohistochemistry for modified tau (phosphorylated at Ser199–202–Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Results: Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson's disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. Conclusion: The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer's therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

Interleukin 1-beta (IL-1β) is a cytokine that modulates breathing when applied systemically or directly into the brain. IL-1β is expressed, along with its receptors, in IL-1β-sensitive respiratory-related circuits, which likely include the inspiratory rhythm generator (the preBotzinger complex, preBotC). Thus, considering that IL-1β might directly modulate preBotC function, we tested whether IL-1β and its endogenous antagonist IL1Ra modulate inspiratory rhythm generation in the brainstem slice preparation containing the preBotC. We found that IL-1β reduces, in a concentration-dependent manner, the amplitude of the fictive inspiratory rhythm generated by the preBotC, which is prevented by IL1Ra. Only a negligible effect on the rhythm frequency was observed at one of the concentrations tested (10 ng/mL). In sum, these findings indicate that IL-1β modulates respiratory rhythm generation. In contrast, IL1Ra did not produce a major effect but slightly increased burst amplitude regularity of the fictive respiratory rhythm. Our findings show that IL-1β modulates breathing by directly modulating the inspiratory rhythm generation. This modulation could contribute to the respiratory response to inflammation in health and disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, which are believed to lead to neural damage that translates into brain dysfunction and cognitive deficits. Brain dysfunction can be evaluated by measuring single-neuron activity (spikes), global neural activity (local field potentials, LFPs) and the interaction between them. Considering that the dynamic interactions between the hippocampal pyramidal cells and lateral septum are important for proper structure function, we used the complete septo-hippocampal preparation from 30-day-old controls and J20-AD transgenic mice to record changes in spiking activity from the lateral septum and its relationship with LFP activity from the CA1 area. The cross-correlation analysis revealed that young J20 transgenic mice exhibit a significant reduction in coupling between lateral septum single-cell activity and neural network activity from the hippocampal CA1. Consistently, phase-lock analysis between lateral septum single-cell activity and CA1 neural network activity showed lower values in J20 transgenic mice. Similarly, the LFP- LFP coherence between CA1 and septum in the theta range showed lower values in J20 animals. Importantly, alterations were found before any detectable signs of cognitive deficits. Our data indicate that the disruption in the communication between hippocampus and rostral lateral septum is an early event in AD pathology and may contribute to the deficits observed during AD.

Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.

Inflammation has been linked to the induction of apneas and Sudden Infant Death Syndrome, whereas proinflammatory mediators inhibit breathing when applied peripherally or directly into the CNS. Considering that peripheral inflammation can activate microglia in the CNS and that this cell type can directly release all proinflammatory mediators that modulate breathing, it is likely that microglia can modulate breathing generation. It might do so also in hypoxia, since microglia are sensitive to hypoxia, and peripheral proinflammatory conditions affect gasping generation and autoresuscitation. Here, we tested whether microglial activation or inhibition affected respiratory rhythm generation. By measuring breathing as well as the activity of the respiratory rhythm generator (the preBotzinger complex), we found that several microglial activators or inhibitors, applied intracisternally in vivo or in the recording bath in vitro, affect the generation of the respiratory rhythms both in normoxia and hypoxia. Furthermore, microglial activation with lipopolysaccharide affected the ability of the animals to autoresuscitate after hypoxic conditions, an effect that is blocked when lipopolysaccharide is co-applied with the microglial inhibitor minocycline. Moreover, we found that the modulation of respiratory rhythm generation induced in vitro by microglial inhibitors was reproduced by microglial depletion. In conclusion, our data show that microglia can modulate respiratory rhythm generation and autoresuscitation.

It has long been known that amyloid s protein (As) plays a key role in Alzheimer's Disease (AD) and in Down Syndrome cognitive decline. Recent findings have shown that soluble forms of As (mostly As oligomers; Aso), rather than insoluble forms (fibrils and plaques), are associated with memory impairments in early stages of AD. Since synaptic plasticity and oscillatory network activity are required for memory formation, consolidation and retrieval, numerous attempts have been made to establish whether or not Aso-induced alterations in synaptic plasticity and oscillatory network activity cause memory impairment. Despite a wealth of uncorrelated experimental evidence, such a relationship remains elusive. Furthermore, the specific cellular mechanisms underlying these disruptions remain to be determined. This review will discuss recent findings about the cellular and network mechanisms involved in Aso-induced alterations of network oscillations and synaptic plasticity that could be responsible for the learning and memory impairments observed in early AD. Additionally, we will review some of the signal transduction pathways involved in these deleterious effects, which are revealing promising therapeutic targets to ease Aso-induced brain dysfunction and treat AD.

Neural networks, including the respiratory network, can undergo a reconfiguration process by just changing the number, the connectivity or the activity of their elements. Those elements can be either brain regions or neurons, which constitute the building blocks of macrocircuits and microcircuits, respectively. The reconfiguration processes can also involve changes in the number of connections and/or the strength between the elements of the network. These changes allow neural networks to acquire different topologies to perform a variety of functions or change their responses as a consequence of physiological or pathological conditions. Thus, neural networks are not hardwired entities, but they constitute flexible circuits that can be constantly reconfigured in response to a variety of stimuli. Here, we are going to review several examples of these processes with special emphasis on the reconfiguration of the respiratory rhythm generator in response to different patterns of hypoxia, which can lead to changes in respiratory patterns or lasting changes in frequency and/or amplitude.

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

Neural networks, including the respiratory network, can undergo a reconfiguration process by just changing the number, the connectivity or the activity of their elements. Those elements can be either brain regions or neurons, which constitute the building blocks of macrocircuits and microcircuits, respectively. The reconfiguration processes can also involve changes in the number of connections and/or the strength between the elements of the network. These changes allow neural networks to acquire different topologies to perform a variety of functions or change their responses as a consequence of physiological or pathological conditions. Thus, neural networks are not hardwired entities, but they constitute flexible circuits that can be constantly reconfigured in response to a variety of stimuli. Here, we are going to review several examples of these processes with special emphasis on the reconfiguration of the respiratory rhythm generator in response to different patterns of hypoxia, which can lead to changes in respiratory patterns or lasting changes in frequency and/or amplitude.

Breathing is a vital function generated and controlled by a brainstem neural network, which is able to adjust its function to fit different metabolic demands. For instance, the pre-Botzinger complex (preBotC) can respond to low oxygen availability (hypoxia) by an initial increase in rhythm frequency followed by a decrease in respiratory efforts that leads to gasping generation. Gasping is essential for autoresuscitation, which has motivated studies of the cellular mechanisms involved in these processes. Hypoxia has different effects on enzymes that participate in the Krebs cycle. In particular, aconitase is downregulated, whereas isocitrate dehydrogenase is unaffected or upregulated under hypoxic conditions. We hypothesized that the application of isocitrate, the product of aconitase and the substrate of isocitrate dehydrogenase as well as an alternative metabolic substrate, might enhance breathing and render it more resistant to hypoxic insult. We tested the effects of isocitrate applied on brainstem slices containing the preBotC as well as its central effects in vivo using plethysmography. Our results show that isocitrate increases the frequency of fictive eupnea and fictive gasping produced by the preBotC in vitro. Moreover, isocitrate increases the amplitude of ventilation in vivo in normoxia, increases ventilation during gasping, and favors autoresuscitation when animals were subjected to asphyxiation. In conclusion, we have found that isocitrate improves ventilation under both normoxic and hypoxic conditions through a mechanism that involves the preBotC and possibly other respiratory neural networks. Thus, isocitrate would be useful to avoid the failure of gasping generation and autoresuscitation in pathological conditions.

Soluble amyloid beta peptide (Aβ) is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM). We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

Understanding the neural mechanisms underlying brain dysfunction induced by amyloid beta-protein (Aβ) represents one of the major challenges for Alzheimer’s disease (AD) research. The most evident symptom of AD is a severe decline in cognition. Cognitive processes, as any other brain function, arise from the activity of specific cell assemblies of interconnected neurons that generate neural network dynamics based on their intrinsic and synaptic properties. Thus, the origin of Aβ-induced cognitive dysfunction, and possibly AD-related cognitive decline, must be found in specific alterations in properties of these cells and their consequences in neural network dynamics. The well-known relationship between AD and alterations in the activity of several neural networks is reflected in the slowing of the electroencephalographic (EEG) activity. Some features of the EEG slowing observed in AD, such as the diminished generation of different network oscillations, can be induced in vivo and in vitro upon Aβ application or by Aβ overproduction in transgenic models. This experimental approach offers the possibility to study the mechanisms involved in cognitive dysfunction produced by Aβ. This type of research may yield not only basic knowledge of neural network dysfunction associated with AD, but also novel options to treat this modern epidemic.

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain's amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

Background Microglia are the resident immunocompetent cells of the CNS and also constitute a unique cell type that contributes to neural network homeostasis and function. Understanding microglia cell-signaling not only will reveal their diverse functions but also will help to identify pharmacological and non-pharmacological tools to modulate the activity of these cells. Methods We undertook a search of bibliographic databases for peer-reviewed research literature to identify microglial activators and their cell-specificity. We also looked for their effects on neural network function and dysfunction. Results We identified several pharmacological targets to modulate microglial function, which are more or less specific (with the proper control experiments). We also identified pharmacological targets that would require the development of new potent and specific modulators. We identified a wealth of evidence about the participation of microglia in neural network function and their alterations in pathological conditions. Conclusion The identification of specific microglia-activating signals provides experimental tools to modulate the activity of this heterogeneous cell type in order to evaluate its impact on other components of the nervous system, and it also helps to identify therapeutic approaches to ease some pathological conditions related to microglial dysfunction.

Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer's disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation.

It is accepted that the main- and accessory- olfactory systems exhibit overlapping responses to pheromones and odorants. We performed whole-cell patch-clamp recordings in adult rat olfactory bulb slices to define a possible interaction between the first central relay of these systems: the accessory olfactory bulb (AOB) and the main olfactory bulb (MOB). This was tested by applying electrical field stimulation in the dorsal part of the MOB while recording large principal cells (LPCs) of the anterior AOB (aAOB). Additional recordings of LPCs were performed at either side of the plane of intersection between the aAOB and posterior-AOB (pAOB) halves, or linea alba, while applying field stimulation to the opposite half. A total of 92 recorded neurons were filled during whole-cell recordings with biocytin and studied at the light microscope. Neurons located in the aAOB (n = 6, 8%) send axon collaterals to the MOB since they were antidromically activated in the presence of glutamate receptor antagonists (APV and CNQX). Recorded LPCs evoked orthodromic excitatory post-synaptic responses (n = 6, aAOB; n = 1, pAOB) or antidromic action potentials (n = 8, aAOB; n = 7, pAOB) when applying field stimulation to the opposite half of the recording site (e.g., recording in aAOB; stimulating in pAOB, and vice-versa). Observation of the filled neurons revealed that indeed, LPCs send axon branches that cross the linea alba to resolve in the internal cellular layer. Additionally, LPCs of the aAOB send axon collaterals to dorsal-MOB territory. Notably, while performing AOB recordings we found a sub-population of neurons (24% of the total) that exhibited voltage-dependent bursts of action potentials. Our findings support the existence of: 1. a direct projection from aAOB LPCs to dorsal-MOB, 2. physiologically active synapses linking aAOB and pAOB, and 3. pacemaker-like neurons in both AOB halves. This work was presented in the form of an Abstract on SfN 2014 (719.14/EE17).

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte’s influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.