European Journal of Neuroscience最新文献

Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester-enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (gas chromatography-mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow-up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease.

Nonhuman animal models continue to be indispensable in neuroscience research for the foreseeable future. In recent years, animal-right activists have been increasing the pressure on politicians and policymakers to phase out animal research. To address this pressure, we should adapt our communication habits, to be more open and transparent about (our) animal research and most importantly to expand the methods we use to communicate about our research and increase the extend of this outreach. In this editorial, we discuss the why and how of animal research communication.

Children with neurodevelopmental disorders, such as developmental coordination disorder (DCD), exhibit gross to fine sensorimotor impairments, reduced physical activity and interactions with the environment and people. This disorder co-exists with cognitive deficits, executive dysfunctions and learning impairments. Previously, we demonstrated in rats that limited amounts and atypical patterns of movements and somatosensory feedback during early movement restriction manifested in adulthood as degraded postural and locomotor abilities, and musculoskeletal histopathology, including muscle atrophy, hyperexcitability within sensorimotor circuitry and maladaptive cortical plasticity, leading to functional disorganization of the primary somatosensory and motor cortices in the absence of cortical histopathology. In this study, we asked how this developmental sensorimotor restriction (SMR) started to impact the integration of multisensory information and the emergence of sensorimotor reflexes in rats. We also questioned the enduring impact of SMR on motor activities, pain and memory. SMR led to deficits in the emergence of swimming and sensorimotor reflexes, the development of pain and altered locomotor patterns and posture with toe-walking, adult motor performance and night spontaneous activity. In addition, SMR induced exploratory hyperactivity, short-term impairments in object-recognition tasks and long-term deficits in object-location tasks. SMR rats displayed minor alterations in histological features of the hippocampus, entorhinal, perirhinal and postrhinal cortices yet no obvious changes in the prefrontal cortex. Taken all together, these results show similarities with the symptoms observed in children with DCD, although further exploration seems required to postulate whether developmental SMR corresponds to a rat model of DCD.

The prevalence of post-traumatic stress disorder (PTSD) is higher in females than males, but pre-clinical models are established almost exclusively in males. This study is aimed to investigate the stress-enhanced fear learning model of PTSD in females. The model mirrors PTSD symptomology in males, whereby prior stress leads to extinction resistant exaggerated contextual fear memory. As stress reactivity is highly relevant to the study and risk for PTSD, females of the stress hyper-reactive Wistar Kyoto More Immobile (WMI) and its nearly isogenic control the Wistar Kyoto Less Immobile (WLI) strains were employed. Prior studies have shown WMI females presenting unchanged or enhanced fear memory in the stress-enhanced fear learning paradigm compared WLIs. The present study confirmed the enhanced fear memory following contextual fear conditioning in WMIs compared to WLI females, but this increased fear memory was neither exaggerated by prior stress nor showed extinction deficit. The novel stressor of a glucose challenge test resulted in subtle strain- and prior stress-induced differences in plasma glucose responses. However, fasting plasma corticosterone levels were lower, and rose slower in response to glucose challenge in WMI females, suggesting a PTSD-like dysfunctional stress response. Hippocampal expressions of genes relevant to both learning and memory and the stress response were decreased in stressed WMIs compared to WLI females, further suggesting a marked dysregulation in stress-related functions like in PTSD. Thus, although WMI females do not show extinction-resistant enhanced fear memory, they do present other characteristics that are relevant to PTSD in women.

Resting-state functional magnetic resonance imaging (rs-fMRI) and brain functional connectome (we use 'brain connectome' hereafter for simplicity) have advanced our understanding of the ageing brain and age-related changes in cognitive function. Previous studies have investigated the association among brain connectome and age, global cognition, and memory function separately. However, very few have predicted age, overall cognitive functioning and memory performance in a single study to better understand their complex relationship. In this cross-sectional study, we applied an exploratory, data-driven method to investigate the brain connectome markers that could predict ageing, overall cognitive functioning assessed as intelligence quotient (IQ, measured by Wechsler Memory Scale) and memory performance assessed as memory quotient (MQ, measured by Wechsler Memory Scale) in a carefully designed, multicentre, normal ageing cohort (n = 313). Our results showed that brain connectome could predict ageing and IQ, but the association with MQ was weak. We found that the connectivity with orbital frontal cortex was associated with both ageing and IQ. Mediation analysis further showed that the brain connectome mediated the relationship between age and overall cognitive functioning, suggesting a protective brain connectomic mechanism for maintaining normal cognitive functions during healthy ageing. This work may shed light on the potential neural correlates of healthy ageing, overall cognitive functioning and memory performance.

Leptomeningeal collaterals (LMCs) are crucial in mitigating the impact of acute ischemic stroke (AIS) by providing alternate blood flow routes when primary arteries are obstructed. This article explores the evolutionary pathophysiology of LMCs, highlighting their critical function in stroke and the genetic and molecular mechanisms governing their development and remodelling. We address the translational challenges of applying animal model findings to human clinical scenarios, emphasizing the need for further research to validate emerging therapies-such as pharmacological agents, gene therapy and mechanical interventions-in clinical settings, aimed at enhancing collateral perfusion. Computational modelling emerges as a promising method for integrating experimental data, which requires precise parameterization and empirical validation. We introduce the 'Evolucollateral Dynamics' hypothesis, proposing a novel framework that incorporates evolutionary biology principles into therapeutic strategies, offering new perspectives on enhancing collateral circulation. This hypothesis emphasizes the role of genetic predispositions and environmental influences on collateral circulation, which may impact therapeutic strategies and optimize treatment outcomes. Future research must incorporate human clinical data to create robust treatment protocols, thereby maximizing the therapeutic potential of LMCs and improving outcomes for stroke patients.

Breathing behaviour is subject to emotional regulation, but the underlying mechanisms remain unclear. Here, we demonstrate a direct relationship between the central amygdala, a major output hub of the limbic system associated with emotional brain function, and the brainstem pre-Bötzinger complex, which generates the fundamental rhythm and pattern for breathing. The connection between these two sites is monosynaptic and inhibitory, involving GABAergic central amygdala neurons whose axonal projections act predominantly via ionotropic GABA_A receptors to produce inhibitory postsynaptic currents in pre-Bötzinger neurons. This pathway may provide a mechanism to inhibit breathing in the context of freezing to assess threats and plan defensive action. The existence of this pathway may further explain how epileptic seizures invading the amygdala cause long-lasting apnea, which can be fatal. Although their ultimate importance awaits further behavioural tests, these results elucidate a link between emotional brain function and breathing, which underlies survival-related behaviour in mammals and pertains to human anxiety disorders.

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement.

The amygdala and raphe nuclei, which play crucial roles in mood regulation, are influenced by serotonergic neurotransmission. Alterations in this neurotransmission are associated with mood disorders. Therefore, using immunohistochemistry and quantitative methods this study was designed to evaluate potential alterations in the expression of serotoninergic markers in the amygdala and raphe nuclei of mice with oestrogen receptor β (ERβ) knock out which exhibit increased anxiety as evidenced by reduced locomotion and increased thigmotaxis. These alterations could either contribute to heightened anxiety or serve as a compensatory strategy for reducing it. The results show that in ERβ knock-out mice, 5-HT1B expression is significantly increased in the amygdala, while 5-HTT expression is significantly decreased in both the amygdala and raphe nuclei. Furthermore, ERβ deficiency does not affect TPH2. In conclusion, serotonin signalling is altered in the amygdala and raphe nuclei of ERβ knock-out females. It seems that an increase in 5-HTT levels has been associated with reduced anxiety, whereas a decrease in 5-HT1B receptors may encourage fear. However, further studies are required to determine the exact role of ERβ in anxiety-related behaviour.