bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
Authors: Lian Hong , Litvinchuk Alexandra , Chiang Angie C.-A. , Aithmitti Nadia , Jankowsky Joanna L. , Zheng Hui 
Published: January 2016

Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron–glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamicsin vitroand amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion ofC3aR. We further demonstrate that Aβ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-κB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Aβ activates astroglial NF-κB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Aβ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions.SIGNIFICANCE STATEMENTThe complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate β-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease.
Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy
Authors: Booth Clair A. , Witton Jonathan , Nowacki Jakub , Tsaneva-Atanasova Krasimira , Jones Matthew W. , Randall Andrew D. , Brown Jonathan T. 
Published: January 2016

The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery ofin vivoandin vitroelectrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration.In vitrorecordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information codingin vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function.SIGNIFICANCE STATEMENTDementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.
Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke
Authors: Ishida Akimasa , Isa Kaoru , Umeda Tatsuya , Kobayashi Kazuto , Kobayashi Kenta , Hida Hideki , Isa Tadashi 
Published: January 2016

Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH.SIGNIFICANCE STATEMENTThe research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.
Tmc1Point Mutation Affects Ca2+Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells
Authors: Corns Laura F. , Johnson Stuart L. , Kros Corné J. , Marcotti Walter 
Published: January 2016

The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. UsingBeethoven(Tmc1Bth/Bth) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca2+permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced.Tmc1Bth/BthOHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated inBthis situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca2+dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current ofTmc1Bth/BthOHCs, whereas raising the intracellular concentration of the Ca2+chelator BAPTA caused smaller increases in resting open probability inBthmutant OHCs than in wild-type control cells. We propose that these observations can be explained by the reduced Ca2+permeability of the mutated MET channel indirectly causing the Ca2+sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca2+influx as a compensatory mechanism.SIGNIFICANCE STATEMENTIn the auditory system, the hair cells convert sound-induced mechanical movement of the hair bundles atop these cells into electrical signals through the opening of mechanically gated ion channels at the tips of the bundles. Although the nature of these mechanoelectrical transducer (MET) channels is still unclear, recent studies implicate transmembrane channel-like protein isoform 1 (TMC1) channels in the mammalian cochlea. Using a mutant mouse model (Beethoven) for progressive hearing loss in humans (DFNA36), which harbors a point mutation in theTmc1gene, we show that this mutation affects the MET channel pore, reducing its Ca2+permeability and its affinity for the permeant blocker dihydrostreptomycin. A number of phenomena that we ascribe to Ca2+-dependent adaptation appear stronger, in compensation for the reduced Ca2+entry.
Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease
Authors: Udupa Kaviraja , Bahl Nina , Ni Zhen , Gunraj Carolyn , Mazzella Filomena , Moro Elena , Hodaie Mojgan , Lozano Andres M. , Lang Anthony E. , Chen Robert 
Published: January 2016

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)–M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼3 and ∼23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼3 ms) and medium (∼23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity.SIGNIFICANCE STATEMENTWe introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼3 ms) and medium (∼23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.
Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy
Authors: Bomben Valerie C. , Aiba Isamu , Qian Jing , Mark Melanie D. , Herlitze Stefan , Noebels Jeffrey L. 
Published: January 2016

Generalized spike-wave seizures involving abnormal synchronization of cortical and underlying thalamic circuitry represent a major category of childhood epilepsy. Inborn errors ofCacna1a, the P/Q-type voltage-gated calcium channel α subunit gene, expressed throughout the brain destabilize corticothalamic rhythmicity and produce this phenotype. To determine the minimal cellular lesion required for this network disturbance, we used neurotensin receptor 1 (Ntsr1) cre-driver mice to ablate floxedCacna1ain layer VI pyramidal neurons, which supply the sole descending cortical synaptic input to thalamocortical relay cells and reticular interneurons and activate intrathalamic circuits. TargetedCacna1aablation in layer VI cells resulted in mice that display a robust spontaneous spike-wave absence seizure phenotype accompanied by behavioral arrest and inhibited by ethosuximide. To verify the selectivity of the molecular lesion, we determined that P/Q subunit proteins were reduced in corticothalamic relay neuron terminal zones, and confirmed that P/Q-mediated glutamate release was reduced at these synapses. Spike-triggered exocytosis was preserved by N-type calcium channel rescue, demonstrating that evoked release at layer VI terminals relies on both P/Q and N-type channels. Whereas intrinsic excitability of the P/Q channel depleted layer VI neurons was unaltered, T-type calcium currents in the postsynaptic thalamic relay and reticular cells were dramatically elevated, favoring rebound bursting and seizure generation. We find that an early P/Q-type release defect, limited to synapses of a single cell-type within the thalamocortical circuit, is sufficient to remodel synchronized firing behavior and produce a stable generalized epilepsy phenotype.SIGNIFICANCE STATEMENTThis study dissects a critical component of the corticothalamic circuit in spike-wave epilepsy and identifies the developmental importance of P/Q-type calcium channel-mediated presynaptic glutamate release at layer VI pyramidal neuron terminals. Genetic ablation ofCacna1ain layer VI neurons produced synchronous spike-wave discharges in the cortex and thalamus that were inhibited by ethosuximide. These mice also displayed N-type calcium channel compensation at descending thalamic synapses, and consistent with other spike-wave models increased low-threshold T-type calcium currents within postsynaptic thalamic relay and reticular neurons. These results demonstrate, for the first time, that preventing the developmental homeostatic switch from loose to tightly coupled synaptic release at a single class of deep layer cortical excitatory output neurons results in generalized spike-wave epilepsy.
Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy
Authors: Booth Clair A. , Ridler Thomas , Murray Tracey K. , Ward Mark A. , de Groot Emily , Goodfellow Marc , Phillips Keith G. , Randall Andrew D. , Brown Jonathan T. 
Published: January 2016

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal–ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30–80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia.SIGNIFICANCE STATEMENTThe medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.
The Neural Representation of Goal-Directed Actions and Outcomes in the Ventral Striatum's Olfactory Tubercle
Authors: Gadziola Marie A. , Wesson Daniel W. 
Published: January 2016

The ventral striatum is critical for evaluating reward information and the initiation of goal-directed behaviors. The many cellular, afferent, and efferent similarities between the ventral striatum's nucleus accumbens and olfactory tubercle (OT) suggests the distributed involvement of neurons within the ventral striatopallidal complex in motivated behaviors. Although the nucleus accumbens has an established role in representing goal-directed actions and their outcomes, it is not known whether this function is localized within the nucleus accumbens or distributed also within the OT. Answering such a fundamental question will expand our understanding of the neural mechanisms underlying motivated behaviors. Here we address whether the OT encodes natural reinforcers and serves as a substrate for motivational information processing. In recordings from mice engaged in a novel water-motivated instrumental task, we report that OT neurons modulate their firing rate during initiation and progression of the instrumental licking behavior, with some activity being internally generated and preceding the first lick. We further found that as motivational drive decreases throughout a session, the activity of OT neurons is enhanced earlier relative to the behavioral action. Additionally, OT neurons discriminate the types and magnitudes of fluid reinforcers. Together, these data suggest that the processing of reward information and the orchestration of goal-directed behaviors is a global principle of the ventral striatum and have important implications for understanding the neural systems subserving addiction and mood disorders.SIGNIFICANCE STATEMENTGoal-directed behaviors are widespread among animals and underlie complex behaviors ranging from food intake, social behavior, and even pathological conditions, such as gambling and drug addiction. The ventral striatum is a neural system critical for evaluating reward information and the initiation of goal-directed behaviors. Here we show that neurons in the olfactory tubercle subregion of the ventral striatum robustly encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward. Our findings are novel in showing that olfactory tubercle neurons participate in such coding schemes and are in accordance with the principle that ventral striatum substructures may cooperate to guide motivated behaviors.
Az elvárások és a hanginger szerepe a binaurális ütemek hallgatása során átélt szubjektív élményekre
Authors: Szabó Gergely , Drótos Gergely , Szabó Csaba 
Published: January 2016

Háttér és célok
A binaurális ütemek a két fül közötti frekvenciakülönbség hatására létrejövő pulzáló hangok. A „binaurális ütem” angol megfelelőinek szavaira az internetes keresési találatok az elmúlt három évben megduplázódtak, ami jól példázza az utóbbi időben egyre inkább növekvő érdeklődést. Ezeket a hangokat feltételezett pszichológiai hatásaik miatt keresik, noha a tudományos adatok ellentmondásosak a témában. Tanulmányunkban arra kerestük a választ, hogy a binaurális ütemek hallgatása milyen szubjektív élményeket vált ki a hallgatóból, és ezeket milyen tényezők befolyásolják, tehát hogy mi a szerepe az elvárásoknak, a hang speciális akusztikai tulajdonságainak, illetve a binaurális ütemek frekvenciatartományának.

Módszer
Jelen tanulmányban két vizsgálatot mutatunk be. Az élményeket a (Phenomenology of Consciousness; PCI) élményfeltáró kérdőívvel és a személyekkel készült interjúk tartalomelemzésével mértük. Az első vizsgálatban 109, a másodikban 159 egyetemi hallgató vett részt. Az első kísérletben az instrukció, a másodikban az ingerek fizikai jellemzőinek hatását vizsgáltuk.

Eredmények
A binaurális ingerlés hatására a személyek élményei szignifikánsan megváltoztak, és az élményeket befolyásolta az instrukció. A különböző akusztikai tulajdonságokkal rendelkező hangok hatásában nem volt különbség.

Következtetések
A binaurális ütemek alkalmasak transzszerű élmények kiváltására. Az átélt élményeket jelentősen befolyásolják az előzetes instrukciók. Az átélt élményeket nem befolyásolja a hangok binaurális tulajdonsága, feltehetőleg az ingerek monotonitása okozza az élményváltozásokat.