Brain and neuroscience advances最新文献

Professor Sir Colin Blakemore was a remarkable neuroscientist, persuasive communicator, and brave advocate for animal research who, sadly, passed away in June 2022 from amyotrophic lateral sclerosis. His work helped establish the concept of neuronal plasticity, which was fundamental to our understanding of the postnatal brain and continues to impact our outlook on neurodegenerative disorders. The BNA2023 Festival of Neuroscience dedicated its last plenary session in his honour, bringing together five prominent neuroscientists whose careers were shaped by Professor Blakemore. Here, we summarise the speakers' reflections on how Colin's support, generosity, and foresight influenced their academic paths, inspired their research, and changed their outlook on life.

A key hallmark of Alzheimer's disease (AD) is the accumulation of hyperphosphorylated tau in neurofibrillary tangles. This occurs alongside neuroinflammation and neurodegeneration. Pathological tau propagates through the AD brain in a defined manner, which correlates with neuron and synapse loss and cognitive decline. One proposed mechanism of tau spread is through synaptically connected brain structures. Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset AD and is associated with increased tau burden. Whether the apolipoprotein E (APOE) genotype influences neurodegeneration via tau spread is currently unknown. Here, we demonstrate that virally expressed human tau (with the P301L mutation) injected into mouse entorhinal cortex at 5-6 months or 15-16 months of age spreads trans-synaptically to the hippocampus by 14 weeks post-injection. Injections of tau in mice expressing human APOE2, APOE3 or APOE4, as well as APOE knock-outs, showed that tau can spread trans-synaptically in all genotypes and that APOE genotype and age do not affect the spread of tau. These data suggest that APOE genotype is not directly linked to synaptic spread of tau in our model, but other mechanisms involving non-cell autonomous manners of tau spread are still possible.

Short-term synaptic plasticity represents a fundamental mechanism in neural information processing and is regulated by neuromodulators. Here, using field recordings from the CA1 region of adult rat hippocampal slices, we show that excitatory synaptic transmission is suppressed by strong but not moderate activation of adenosine A₁ receptors by 2-Chloro-N⁶-cyclopentyladenosine (CCPA) more in the dorsal than the ventral hippocampus; in contrast, both mild and strong activation of GABA_B receptors by baclofen (1 μM, 10 μM) suppress synaptic transmission more in the ventral than the dorsal hippocampus. Using a 10-pulse stimulation train of variable frequency, we found that CCPA modulates short-term synaptic plasticity independently of the suppression of synaptic transmission in both segments of the hippocampus and at stimulation frequencies greater than 10 Hz. However, specifically regarding the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D) we found significant drug action before but not after adjusting conditioning responses to control levels. Activation of GABA_BRs by baclofen suppressed synaptic transmission more in the ventral than the dorsal hippocampus. Furthermore, relatively high (10 μM) but not low (1 μM) baclofen concentration enhanced both PPR and FF in both hippocampal segments at stimulation frequencies greater than 1 Hz, independently of the suppression of synaptic transmission by baclofen. These results show that A₁Rs and GABA_BRs control synaptic transmission more effectively in the dorsal and the ventral hippocampus, respectively, and suggest that these receptors modulate PPR and FF/D at different frequency bands of afferent input, in both segments of the hippocampus.

Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non-rewarded trial, and mostly after a previous premature trial. However, contrary to the frustration hypothesis of negative urgency, increasing the probability of reinforcement (p(R)) from p(R) = 0.5 to p(R) = 1 increased the number of premature responses in each session. Micro and macro levels of analyses revealed that impulsivity in the five-choice serial reaction time task is governed by at least two processes, one dependent on the overall level of reinforcement hypothesised to determine the state of behavioural activation, the second dependent on trial-by-trial outcomes consistent with negative urgency effects. These processes may depend on distinct neurobiological mechanisms and have relevance for neuropsychiatric disorders that implicate impulsive behaviours dependent on positive and negative affective states.

It remains unclear whether the negative reinforcement pathway to problematic drinking exists, and if so, for whom. One idea that has received some support recently is that people who tend to act impulsively in response to negative emotions (i.e. people high in negative urgency) may specifically respond to negative affect with increased alcohol consumption. We tested this idea in a preregistered secondary data analysis of two ecological momentary assessment studies using college samples. Participants (N = 226) reported on their current affective state multiple times per day and also the following morning reported alcohol use of the previous night. We assessed urgency both at baseline and during the momentary affect assessments. Results from our Bayesian model comparison procedure, which penalises increasing model complexity, indicate that no combination of the variables of interest (negative affect, urgency, and the respective interactions) outperformed a baseline model that included two known demographic predictors of alcohol use. A non-preregistered exploratory analysis provided some evidence for the effect of daily positive affect, positive urgency, as well as their interaction on subsequent alcohol use. Taken together, our results suggest that college students' drinking may be better described by a positive rather than negative reinforcement cycle.

Impulsive urgency describes the tendency to act rashly when experiencing extreme emotions. This Australian study aimed to investigate the predictive utility of impulsivity, including impulsive urgency (positive and negative), across a range of problem behaviours. Data from two community samples, one retrospective (n = 281) and one current (n = 604), were analysed using hierarchical regression to determine which facets of impulsivity, as assessed with a comprehensive scale (i.e. negative urgency, positive urgency, lack or premeditation, lack of perseverance, and sensation seeking), best predicted a series of problem behaviours (i.e. problem gambling, disorderly alcohol use, online gambling disorder, obsessive-compulsive disorder behaviours, and social media addiction). The impulsive urgency facets were shown to be significant predictors across the behaviours examined. More specifically, negative urgency was the strongest predictor of disorderly alcohol use, obsessive-compulsive disorder behaviours, and social media addiction. Positive urgency was associated with problem gambling and online gambling disorder behaviours. These findings suggest that impulsive urgency is a key contributing factor in many behavioural problems and that the valence of the urgency is an important consideration when addressing a broad range of psychopathologies.

Attention involves both an ability to selectively focus on relevant information and simultaneously ignore irrelevant information (i.e. inhibitory control). Many factors impact inhibitory control such as individual differences, relative timing of stimuli presentation, distractor characteristics, and participant age. Previous research with young adults responding to an attention-demanding rapid serial visual presentations of pictures superimposed with task-irrelevant words evaluated the extent to which unattended information may be subject to inhibitory control. Surprise recognition tests following the rapid serial visual presentation task showed that recognition for unattended words presented with non-targets (i.e. non-aligned or 'NA' words) during the rapid serial visual presentation task were recognised at chance levels. However, when the unattended words were infrequently paired with the attended picture targets (i.e. target-aligned or 'TA' words), recognition rates were significantly below chance and significantly lower compared to NA words, suggesting selective inhibitory control for the previously unattended TA words. The current study adapted this paradigm to compare healthy younger and older adults' ability to engage in inhibitory control. In line with previous research, younger adults demonstrated selective inhibition with recognition rates for TA words significantly lower than NA words and chance, while NA words were recognised at chance levels. However, older adults showed no difference in recognition rates between word types (TA versus NA). Rather all items were recognised at rates significantly below chance suggesting inhibited recognition for all unattended words, regardless of when they were presented during the primary task. Finally, older adults recognised significantly fewer NA words compared to young adults. These findings suggest that older adults may experience a decline in their ability to selectively inhibit the processing of irrelevant information, while maintaining the capacity to exercise global inhibition over unattended lexical information.

Cannabis has been shown to cause structural and functional neurocognitive changes in heavy users. Cannabis use initiation aligns with brain development trajectories; therefore, it is imperative that the potential neurological implications of cannabis use are understood. Males and females reach neurodevelopmental milestones at different rates making it necessary to consider biological sex in all cannabis and brain-based research. Through use of a systamatic review in accordance with PRISMA guidelines, we aimed to understand the interaction between biological sex and cannabis use on brain-based markers. In total, 18 articles containing a sex-based analysis of cannabis users were identified. While the majority of studies (n = 11) reported no sex by cannabis use interactions on brain-based markers, those that reported findings (n = 8) suggest females may be more susceptible to cannabis' neurotoxic effects. Unfortunately, a large portion of the literature was excluded due to no sex-based analysis. In addition, studies that reported no sex differences often contained a reduced number of females which may result in some studies being underpowered for sex-based analyses, making it difficult to draw firm conclusions. Suggestions to improve cannabis and sex-based reseach are proposed.

Synapse loss is associated with cognitive decline in Alzheimer's disease, and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human Alzheimer's disease brain tissue, but the mechanisms leading from Aβ to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltage-gated potassium channel subtype 3.4 (Kv3.4) may play a role in Aβ-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aβ synaptotoxicity. Using adeno-associated virus and clustered regularly interspaced short palindromic repeats technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial Alzheimer's disease-associated mutations in amyloid precursor protein and presenilin-1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in Alzheimer's disease brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human Alzheimer's disease and control brain and is associated with synapses in human induced pluripotent stem cell-derived cortical neurons. We also noted morphological changes in induced pluripotent stem cell neurones challenged with human Alzheimer's disease-derived brain homogenate containing Aβ but, in this in vitro model, total mRNA levels of Kv3.4 were found to be reduced, perhaps as an early compensatory mechanism for Aβ-induced damage. Overall, our results suggest that approaches to reduce Kv3.4 expression and/or function in the Alzheimer's disease brain could be protective against Aβ-induced synaptic alterations.