Current research in neurobiology最新文献

There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.

Laser thermal ablation has become a prominent neurosurgical treatment approach, but in epilepsy patients it cannot currently be safely implemented with intracranial recording electrodes that are used to study interictal or epileptiform activity. There is a pressing need for computational models of laser interstitial thermal therapy (LITT) with and without intracranial electrodes to enhance the efficacy and safety of optical neurotherapies. In this paper, we aimed to build a biophysical bioheat and ray optics model to study the effects of laser heating in the brain, with and without intracranial electrodes in the vicinity of the ablation zone during the LITT procedure. COMSOL Multiphysics finite element method (FEM) solver software was used to create a bioheat thermal model of brain tissue, with and without blood flow incorporation via Penne's model, to model neural tissue response to laser heating. We report that the close placement of intracranial electrodes can increase the maximum temperature of the brain tissue volume as well as impact the necrosis region volume if the electrodes are placed too closely to the laser coupled diffuse fiber tip. The model shows that an electrode displacement of 4 mm could be considered a safe distance of intracranial electrode placement away from the LITT probe treatment area. This work, for the first time, models the impact of intracranially implanted recording electrodes during LITT, which could improve the understanding of the LITT treatment procedure on the brain's neural networks a sufficient safe distance to the implanted intracranial recording electrodes. We recommend modeling safe distances for placing the electrodes with respect to the infrared laser coupled diffuse fiber tip.

Investigating frontal EEG asymmetry as a possible biomarker of cognitive control abilities is especially important in ecological contexts such as school and work. We used a novel approach combining judgment performance and hemispheric frontal event-related potential (ERP) P300 asymmetry (fP3As) to evaluate aspects of cognitive control (i.e., repetition and switching) in adolescent females over a two-week ordinary school period. While undergoing electroencephalographic recording, students performed a word-colour “Stroop-like” congruence judgment task during morning and afternoon sessions, on Mondays and Wednesdays. Proportion of incongruence and congruence trials was 75% and 25%, respectively. ERP analysis revealed larger “novelty” right hemispheric fP3As amplitude for infrequent congruence but equivalent or significantly smaller than left hemispheric fP3As amplitude for frequent incongruence. RTs increased with extent of right fP3As shift. Behaviorally, repeat trial pairs (i.e., congruent followed by congruent, incongruent followed by incongruent) generally did not differ by time or day and were associated with near-ceiling accuracy. In contrast, switch trial pairs (i.e., congruent followed by incongruent, incongruent followed by congruent) in the afternoon were slower and associated with lower accuracy at the expected 75% criterion rate (i.e., judging incongruence by default), dropping significantly below 75% in the mornings. Crucially, compared to afternoon, morning fP3As patterns did not change adaptively with switch trial pairs. Although retroactive switching during congruence judgment was affected at all testing times, we conclude it was most impaired in the mornings of both early and mid school weeks, supporting misalignment between adolescent circadian cycle and school start time. We discuss some implications for optimal learning of adolescents at school.

Background

In children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex.

Methods

Hearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC).

Results

In the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p < 0.05). Deafened rats showed significantly more play fighting during development (p < 0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p > 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p < 0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p < 0.05).

Conclusions

Hearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are often non-responsive to medication; however, our understanding of the relation between menstrual cycle and seizure generation (i.e. ictogenesis) remains limited. We employed here field potential recordings in the in vitro 4-aminopyridine model of epileptiform synchronization in female mice (P60–P130) and found that: (i) the estrous phase favors ictal activity in the entorhinal cortex; (ii) these ictal discharges display an onset pattern characterised by the presence of chirps that are thought to mirror synchronous interneuron firing; and (iii) blocking estrogen receptor β-mediated signaling reduces ictal discharge duration. Our findings indicate that the duration of 4AP-induced ictal discharges, in vitro, increases during the estrous phase, which corresponds to the human peri-ovulatory period. We propose that these effects are caused by the presumptive enhancement of interneuron excitability due to increased estrogen receptor β-mediated signaling.

Iron is an important cofactor for many proteins and is used to create Fe-S clusters and heme prosthetic groups that enzymes use to catalyze enzymatic reactions. Proteins involved in the import, export, and sequestration of iron are regulated by Iron Regulatory Proteins (IRPs). Recently, a patient with bi-allelic loss of function mutations in IREB2 leading to the absence of IRP2 protein was discovered. The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy. Several more IREB2 deficient patients subsequently identified manifested similar neurological problems. To better understand the manifestations of this novel neurological disease, we subjected an Irp2-null mouse model to extensive behavioral testing. Irp2-null mice had a significant motor deficit demonstrated by reduced performance on rotarod and hanging wire tests. Somatosensory function was also compromised in hot and cold plate assays. Their spatial search strategy was impaired in the Barnes maze and they exhibited a difficulty in flexibly adapting their response in the operant touchscreen reversal learning task. The latter is a cognitive behavior known to require an intact prefrontal cortex. These results suggest that loss of Irp2 in mice causes motor and behavioral deficits that faithfully reflect the IREB2 patient's neurodegenerative disorder.

We established a longitudinal acute slice preparation of transgenic mouse optic nerve to characterize membrane properties and coupling of glial cells by patch-clamp and dye-filling, complemented by immunohistochemistry. Unlike in cortex or hippocampus, the majority of EGFP + cells in optic nerve of the hGFAP-EGFP transgenic mouse, a tool to identify astrocytes, were characterized by time and voltage dependent K⁺-currents including A-type K⁺-currents, properties previously described for NG2 glia. Indeed, the majority of transgene expressing cells in optic nerve were immunopositive for NG2 proteoglycan, whereas only a minority show GFAP immunoreactivity. Similar physiological properties were seen in YFP + cells from NG2-YFP transgenic mice, indicating that in optic nerve the transgene of hGFAP-EGFP animals is expressed by NG2 glia instead of astrocytes. Using Cx43kiECFP transgenic mice as another astrocyte-indicator revealed that astrocytes had passive membrane currents. Dye-filling showed that hGFAP-EGFP+ cells in optic nerve were coupled to none or few neighboring cells while hGFAP-EGFP+ cells in the cortex form large networks. Similarly, dye-filling of NG2-YFP+ and Cx43-CFP+ cells in optic nerve revealed small networks. Our work shows that identification of astrocytes in optic nerve requires distinct approaches, that the cells express membrane current patterns distinct from cortex and that they form small networks.

Tonotopic organization of the auditory cortex has been extensively studied in many mammalian species using various methodologies and physiological preparations. Tonotopy mapping in primates, however, is more limited due to constraints such as cortical folding, use of anesthetized subjects, and mapping methodology. Here we applied a combination of through-skull and through-window intrinsic optical signal imaging, wide-field calcium imaging, and neural probe recording techniques in awake marmosets (Callithrix jacchus), a New World monkey with most of its auditory cortex located on a flat brain surface. Coarse tonotopic gradients, including a recently described rostral-temporal (RT) to parabelt gradient, were revealed by the through-skull imaging of intrinsic optical signals and were subsequently validated by single-unit recording. Furthermore, these tonotopic gradients were observed with more detail through chronically implanted cranial windows with additional verifications on the experimental design. Moreover, the tonotopy mapped by the intrinsic-signal imaging methods was verified by wide-field calcium imaging in an AAV-GCaMP labeled subject. After these validations and with further effort to expand the field of view more rostrally in both windowed and through-skull subjects, an additional putative tonotopic gradient was observed more rostrally to the area RT, which has not been previously described by the standard model of tonotopic organization of the primate auditory cortex. Together, these results provide the most comprehensive data of tonotopy mapping in an awake primate species with unprecedented coverage and details in the rostral proportion and support a caudal-rostrally arranged mesoscale organization of at least three repeats of functional gradients in the primate auditory cortex, similar to the ventral stream of primate visual cortex.

A fundamental problem in neuroscience is how neurons select for their many inputs. A common assumption is that a neuron's selectivity is largely explained by differences in excitatory synaptic input weightings. Here we describe another solution to this important problem. We show that within the first order visual thalamus, the type of inhibition provided by thalamic interneurons has the potential to alter the input selectivity of thalamocortical neurons. To do this, we developed conductance injection protocols to compare how different types of synchronous and asynchronous GABA release influence thalamocortical excitability in response to realistic patterns of retinal ganglion cell input. We show that the asynchronous GABA release associated with tonic inhibition is particularly efficient at maintaining information content, ensuring that thalamocortical neurons can distinguish between their inputs. We propose a model where alterations in GABA release properties results in rapid changes in input selectivity without requiring structural changes in the network.