Neuroscience Insights最新文献

Among the various chemicals that are commonly used as pesticides, organophosphates (OPs), and to a lesser extent, carbamates, are most frequently associated with adverse long-term neurological consequences. OPs and the carbamate, pyridostigmine, used as a prophylactic drug against potential nerve agent attacks, have also been implicated in Gulf War Illness (GWI), which is often characterized by chronic neurological symptoms. While most OP- and carbamate-based pesticides, and pyridostigmine are relatively potent acetylcholinesterase inhibitors (AChEIs), this toxicological mechanism is inadequate to explain their long-term health effects, especially when no signs of acute cholinergic toxicity are exhibited. Our previous work suggests that a potential mechanism of the long-term neurological deficits associated with OPs is impairment of axonal transport (AXT); however, we had not previously evaluated carbamates for this effect. Here we thus evaluated the carbamate, physostigmine (PHY), a highly potent AChEI, on AXT using an in vitro neuronal live imaging assay that we have previously found to be very sensitive to OP-related deficits in AXT. We first evaluated the OP, diisopropylfluorophosphate (DFP) (concentration range 0.001-10.0 µM) as a reference compound that we found previously to impair AXT and subsequently evaluated PHY (concentration range 0.01-100 nM). As expected, DFP impaired AXT in a concentration-dependent manner, replicating our previously published results. In contrast, none of the concentrations of PHY (including concentrations well above the threshold for impairing AChE) impaired AXT. These data suggest that the long-term neurological deficits associated with some carbamates are not likely due to acute impairments of AXT.

Hypertrophic olivary degeneration is a rare condition caused by a lesion in the Guillain-Mollaret triangle which leads to trans-synaptic degeneration resulting in the degenerative hypertrophy of the inferior olivary nucleus. This condition presents clinically with palatal tremor but can also produce ocular myoclonus or cerebellar signs. While any lesion that occurs within the Guillian-Mollaret triangle and results in the deafferentation of the inferior olive can lead to hypertrophic olivary degeneration, the most common etiologies include ischemic and hemorrhagic stroke, vascular malformation, neoplasm, and iatrogenic injury related to surgery. We report a series of 7 patients who presented with this condition bilaterally on MRI imaging, including 1 case which represents the first report of toxoplasmosis leading to the development of bilateral hypertrophic olivary degeneration and only the third reported case, unilateral or bilateral, related to an infectious etiology.

Considering its small size relative to the rest of the body, the mammalian brain has a disproportionately high energy requirement. This energy is supplied to the brain mainly in the form of glucose through the principal cerebral glucose transporter, Glut1. Inactivation of even a single copy of the Glut1 gene, SLC2A1, has dire consequences for the brain, starving cerebral neurons of energy and triggering the debilitating neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease serves as an excellent paradigm to study the larger family of brain energy failure syndromes. Here we review how studies of Glut1 DS are proving instructive to the brain's energy needs, focusing first on the requirements, both spatial and temporal of the transporter, second, on proposed mechanisms linking low Glut1 to brain dysfunction and, finally on efforts to treat the disease and thus restore nutritional support to the brain. These studies promise not only to inform mechanisms and treatments for the relatively rare Glut1 DS but also the myriad other conditions involving the Glut1 protein.

Alcohol use disorder is associated with pathophysiological changes in the dopaminergic system. Orthodenticle homeobox 2 (OTX2) is a transcription factor important for the development of dopaminergic neurons residing in the ventral tegmental area (VTA), a critical region of the brain involved in drug reinforcement. Previous studies have demonstrated that ethanol exposure during embryonic development reduces Otx2 mRNA levels in the central nervous system. We hypothesized that levels of OTX2 would be altered by binge-like ethanol consumption in adult animals. To test this, Otx2 mRNA and protein levels in the mouse VTA were measured by quantitative real-time PCR and western blotting, respectively, after mice drank ethanol for 4 days in a procedure that elicits binge levels of ethanol consumption (drinking in the dark). Expression of known and putative OTX2 transcriptional target genes (Sema3c, Wnt1, and Mdk) were also measured in the VTA after ethanol drinking. Otx2 mRNA and protein levels were elevated in the VTA 24 hours after the fourth drinking session and there was a corresponding increase in the expression of Mdk transcript. Interestingly, Wnt1 transcript was elevated in the VTA immediately after the fourth drinking session but returned to control levels 24 hours later. We next investigated if viral-mediated reduction of Otx2 in the mouse VTA would alter ethanol or sucrose intake. Lentiviral vectors expressing a shRNA targeting Otx2 or a control shRNA were injected into the VTA and mice were tested in the drinking in the dark protocol for ethanol and sucrose drinking. Reducing levels of OTX2 in the VTA did not alter ethanol or sucrose consumption. One limitation is that the extent of OTX2 reduction may not have been sufficient. Although OTX2 in the VTA may not play a role in binge-like drinking in adult mice, OTX2 could contribute to ethanol-induced transcriptional changes in this region.

Alcohol Use Disorder (AUD) is a debilitating disorder that manifests as problematic patterns of alcohol use. At the core of AUD's behavioral manifestations are the profound structural, physiological, cellular, and molecular effects of alcohol on the brain. While the field has made considerable progress in understanding the neuromolecular targets of alcohol we still lack a comprehensive understanding of alcohol's actions and effective treatment strategies. Drosophila melanogaster is a powerful model for investigating the neuromolecular targets of alcohol because flies model many of the core behavioral elements of AUD and offer a rich genetic toolkit to precisely reveal the in vivo molecular actions of alcohol. In this review, we focus on receptors and channels that are often targeted by alcohol within the brain. We discuss the general roles of these proteins, their role in alcohol-associated behaviors across species, and propose ways in which Drosophila models can help advance the field.

We evaluated the outcomes of an intervention using a serious game designed to be played on iPads for improving spatial reorientation by training users to integrate geometry of the environment, instead of relying solely on featural cues. Using data logged online through a clinical study of using this game, the effect of training among 16 older adults (69.3 ± 6.4 years, 4 males), who played the game repeatedly (self-administered) over a period of 8 weeks, was investigated. The game contains a hexagonal room with 3 objects, textured walls, and grids on the floor, which are removed one by one as the participant played the game. In each level, the room also rotates such that the viewpoint of the user is different from that of the previous level. Participants cannot play a higher level unless they make no mistake during the trials of the lower test level. In addition to data of older adults available from that clinical trial, we recruited 16 young adults (27.3 ± 5.6 years, 4 males) to play the game for 5 sessions and compared their results with those of the older adults. We evaluated the error type made in each test level and the scores for each session among older adults. Further, we compared the frequency of each error type between young and older adults during the test levels that a landmark adjacent to the target was removed over the first 5 sessions. The results of older adults' performance suggest they learned to make fewer mistakes over the sessions. Also, both young and older adults learned to integrate the geometrical cues rather than relying on the landmark cue adjacent to the target to find the target. Overall, the results indicate the designed hexagonal room game can enhance spatial cognition among all age groups of adults.

An issue commonly expressed by hearing aid users is a difficulty to understand speech in complex hearing scenarios, that is, when speech is presented together with background noise or in situations with multiple speakers. Conventional hearing aids are already designed with these issues in mind, using beamforming to only enhance sound from a specific direction, but these are limited in solving these issues as they can only modulate incoming sound at the cochlear level. However, evidence exists that age-related hearing loss might partially be caused later in the hearing processes due to brain processes slowing down and becoming less efficient. In this study, we tested whether it would be possible to improve the hearing process at the cortical level by improving neural tracking of speech. The speech envelopes of target sentences were transformed into an electrical signal and stimulated onto elderly participants' cortices using transcranial alternating current stimulation (tACS). We compared 2 different signal to noise ratios (SNRs) with 5 different delays between sound presentation and stimulation ranging from 50 ms to 150 ms, and the differences in effects between elderly normal hearing and elderly hearing impaired participants. When the task was performed at a high SNR, hearing impaired participants appeared to gain more from envelope-tACS compared to when the task was performed at a lower SNR. This was not the case for normal hearing participants. Furthermore, a post-hoc analysis of the different time-lags suggest that elderly were significantly better at a stimulation time-lag of 150 ms when the task was presented at a high SNR. In this paper, we outline why these effects are worth exploring further, and what they tell us about the optimal tACS time-lag.

Gulf War Illness (GWI) refers to a multi-system disorder that afflicts approximately 30% of First Gulf War (GW) veterans. Amongst the symptoms exhibited, mood and memory impairment are commonly reported by GW veterans. Exposure to organophosphate (OP) compounds which target the cholinergic system is considered a leading cause for GWI symptoms. It is hypothesized that chronic OP-based war-time stimulation of cholinergic signaling led to recruitment of excitatory glutamatergic signaling and other downstream signaling cascades leading to neuronal injury, neuroinflammation, generation of reactive oxygen species, oxidative stress, and mitochondrial damage within the central nervous system. These findings have been observed in both experimental models and GWI veterans. In this context the role of calcium (Ca²⁺) signaling in GWI has come to the forefront. Here we present our Ca²⁺ hypothesis of GWI that suggests sustained neuronal Ca²⁺ elevations serve as a molecular trigger for pathological synaptic plasticity that has allowed for the persistence of GWI symptoms. Subsequently we discuss that therapeutic targeting of Ca²⁺ homeostatic mechanisms provides novel targets for effective treatment of GWI-related neurological signs in our rodent model.

Neurotrophins, a class of growth factor proteins that control neuronal proliferation, morphology, and apoptosis, are found ubiquitously throughout the nervous system. One particular neurotrophin (NT-3) and its cognate tyrosine receptor kinase (TrkC) have recently received attention as a possible therapeutic target for synaptopathic sensorineural hearing loss. Additionally, research shows that NT-3-TrkC signaling plays a role in establishing the sensory organization of frequency topology (ie, tonotopic order) in the cochlea of the peripheral inner ear. However, the neurotrophic effects of NT-3 on central auditory properties are unclear. In this study we examined whether NT-3-TrkC signaling affects the intrinsic electrophysiological properties at a first-order central auditory structure in chicken, known as nucleus magnocellularis (NM). Here, the expression pattern of specific neurotrophins is well known and tightly regulated. By using whole-cell patch-clamp electrophysiology, we show that NT-3 application to brainstem slices does not affect intrinsic properties of high-frequency neuronal regions but had robust effects for low-frequency neurons, altering voltage-dependent potassium functions, action potential repolarization kinetics, and passive membrane properties. We suggest that NT-3 may contribute to the precise establishment and organization of tonotopy in the central auditory pathway by playing a specialized role in regulating the development of intrinsic neuronal properties of low-frequency NM neurons.