Brain Structure and Function

Less disruption of the blood–brain barrier (BBB) after severe ischemic stroke is one of the beneficial outcomes of ischemic preconditioning (IP). However, the effect of IP on tight junctions (TJs), which regulate paracellular permeability of the BBB, is not well understood. In the present study, we examined IP-induced changes in TJs before and after middle cerebral artery occlusion (MCAO) in mice, and the association between changes in TJs and tolerance to a subsequent insult. After IP, we found decreased levels of transmembrane TJ proteins occludin and claudin-5, and widened gaps of TJs with perivascular swelling at the ultrastructural level in the brain. An inflammatory response was also observed. These changes were reversed by inhibition of extracellular signal-regulated kinase1/2 (ERK1/2) via the specific ERK1/2 inhibitor U0126. After MCAO, reduced brain edema and inflammatory responses were associated with altered levels of angiogenic factors and cytokines in preconditioned brains. Pretreatment with U0126 reversed the neuroprotective effects of IP against MCAO. These findings suggest that ERK1/2 activation has a pivotal role in IP-induced changes in TJs and inflammatory response, which serve to protect against BBB breakdown and inflammation after ischemic stroke.

Cortical expansion, both in absolute terms and in relation to subcortical structures, is considered a major trend in mammalian brain evolution with important functional implications, given that cortical computations should add complexity and flexibility to information processing. Here, we investigate the numbers of neurons that compose 4 structures in the visual pathway across 11 non-human primate species to determine the scaling relationships that apply to these structures and among them. We find that primary visual cortex, area V1, as well as the superior colliculus (SC) and lateral geniculate nucleus scale in mass faster than they gain neurons. Areas V1 and MT gain neurons proportionately to the entire cerebral cortex, and represent fairly constant proportions of all cortical neurons (36 and 3 %, respectively), while V1 gains neurons much faster than both subcortical structures examined. Larger primate brains therefore have increased ratios of cortical to subcortical neurons involved in processing visual information, as observed in the auditory pathway, but have a constant proportion of cortical neurons dedicated to the primary visual representation, and a fairly constant ratio of about 45 times more neurons in primary visual than in primary auditory cortical areas.

In addition to motor functions, it has become clear that in humans the cerebellum plays a significant role in cognition too, through connections with associative areas in the cerebral cortex. Classical anatomy indicates that neo-cerebellar regions are connected with the contralateral cerebral cortex through the dentate nucleus, superior cerebellar peduncle, red nucleus and ventrolateral anterior nucleus of the thalamus. The anatomical existence of these connections has been demonstrated using virus retrograde transport techniques in monkeys and rats ex vivo. In this study, using advanced diffusion MRI tractography we show that it is possible to calculate streamlines to reconstruct the pathway connecting the cerebellar cortex with contralateral cerebral cortex in humans in vivo. Corresponding areas of the cerebellar and cerebral cortex encompassed similar proportion (about 80 %) of the tract, suggesting that the majority of streamlines passing through the superior cerebellar peduncle connect the cerebellar hemispheres through the ventrolateral thalamus with contralateral associative areas. This result demonstrates that this kind of tractography is a useful tool to map connections between the cerebellum and the cerebral cortex and moreover could be used to support specific theories about the abnormal communication along these pathways in cognitive dysfunctions in pathologies ranging from dyslexia to autism.

Animal studies suggest that serotonin, mediated by the 5-HT1A receptor, plays a key role in spatial learning and memory. The role of serotonin in spatial memory in humans has, however, been less well studied. This study examined the relationship between serotonin receptor density in the human brain and spatial learning and memory using the 5-HT1A receptor ligand 18F-4-(2′-methoxyphenyl)-1-[2′-(N-2-pyridinyl)-p-fluorobenzamido]-ethyl-piperazine ([18F] MPPF) and positron emission tomography (PET). Ten neurologically healthy individuals underwent two [18F] MPPF PET scans, one while performing a task which involves processing of high-level spatial information (‘house scan’), and one while performing a task which involves processing of low-level spatial information (‘tunnel scan’). Navigation, recall of arbitrary associations between objects and their spatial location, and ability to draw a plan of the environment were tested following the house scan. 5-HT1A receptor binding did not differ significantly between processing high and low levels of spatial information. Hippocampal asymmetry in [18F] MPPF binding, however, was associated with memory for object–location associations; lower right than left hippocampal binding potential (BPND) was related to better memory performance. We conclude that hippocampal serotonergic function plays a role in a fundamental component of human spatial memory, the ability to recall the location of encountered objects.

Nhiều nghiên cứu đã chỉ ra rằng bệnh nhân mắc chứng suy giảm nhận thức nhẹ mất trí nhớ (aMCI), một tiền đề tiềm năng của bệnh Alzheimer (AD), đặc biệt gặp khó khăn trong việc nhớ các mối quan hệ giữa các đối tượng và việc sử dụng các mục tiêu cảm xúc có thể hỗ trợ trí nhớ ở bệnh nhân mắc AD. Chúng tôi liên kết những phát hiện này bằng cách kiểm tra việc học thông qua phản hồi tích cực và tiêu cực ở bệnh nhân aMCI, đồng thời khám phá các cơ sở giải phẫu của nó bằng cách sử dụng hình ảnh tensor khuếch tán và phân tích đường đi. So với nhóm chứng khỏe mạnh, bệnh nhân aMCI đơn lĩnh vực bị suy giảm khả năng học hỏi từ phản hồi tích cực, trong khi khả năng học hỏi từ kết quả tiêu cực vẫn được bảo tồn. Trong các đường dẫn trong mạch não liên quan đến học hỏi phản hồi, đã quan sát thấy cấu trúc chất trắng bất thường trong các bó dây nối amygdala bên trái với hồi hippocampus và vỏ não entorhinal. Ở tất cả các tham gia viên, sự giảm tính toàn vẹn của chất trắng trong bó dây bên trái này đặc biệt liên quan đến việc học từ kết quả tích cực. Cấu trúc của các bó dây bên phải giữa amygdala và vỏ não entorhinal có liên quan đến việc học từ phản hồi tiêu cực và không bị ảnh hưởng ở bệnh nhân aMCI. Kết quả của chúng tôi cung cấp cái nhìn mới về cách các kết nối giải phẫu có thể góp phần vào các khía cạnh học hỏi bị suy giảm và được bảo tồn trong quá trình bệnh Alzheimer giai đoạn đầu và chỉ ra các cơ chế bù đắp tiềm năng.

Exercising regularly is a highly effective strategy for maintaining cognitive health throughout the lifespan. Over the last 20 years, many molecular, physiological and structural changes have been documented in response to aerobic exercise training in humans and animals, particularly in the hippocampus. However, how exercise produces such neurological changes remains elusive. A recent line of investigation has suggested that muscle-derived circulating factors cross into the brain and may be the key agents driving enhancement in synaptic plasticity and hippocampal neurogenesis from aerobic exercise. Alternatively, or concurrently, the signals might originate from within the brain itself. Physical activity also produces instantaneous and robust neuronal activation of the hippocampal formation and the generation of theta oscillations which are closely correlated with the force of movements. The repeated acute activation of the hippocampus during physical movement is likely critical for inducing the long-term neuroadaptations from exercise. Here we review the evidence which establishes the association between physical movement and hippocampal neuronal activation and discuss implications for long-term benefits of physical activity on brain function.

Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular β-amyloid (Aβ) infusion model of Alzheimer’s disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aβ-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aβ-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.

Age-related changes in the microstructural organization of the corpus callosum (CC) may explain declines in bimanual motor performance associated with normal aging. We used diffusion tensor imaging in young (n = 33) and older (n = 33) adults to investigate the microstructural organization of seven specific CC subregions (prefrontal, premotor, primary motor, primary sensory, parietal, temporal and occipital). A set of bimanual tasks was used to assess various aspects of bimanual motor functioning: the Purdue Pegboard test, simultaneous and alternating finger tapping, a choice reaction time test and a complex visuomotor tracking task. The older adults showed age-related deficits on all measures of bimanual motor performance. Correlation analyses within the older group showed that white matter fractional anisotropy of the CC occipital region was associated with bimanual fine manipulation skills (Purdue Pegboard test), whereas better performance on the other bimanual tasks was related to higher fractional anisotropy in the more anterior premotor, primary motor and primary sensory CC subregions. Such associations were less prominent in the younger group. Our findings suggest that structural alterations of subregional callosal fibers may account for bimanual motor declines in normal aging.

Perivascular endfeet of astrocytes are enriched with aquaporin-4 (AQP4)—a water channel that is critically involved in water transport at the brain–blood interface and that recently was identified as a key molecule in a system for waste clearance. The factors that determine the size of the perivascular AQP4 pool remain to be identified. Here we show that the size of this pool differs considerably between brain regions, roughly mirroring regional differences in Aqp4 mRNA copy numbers. We demonstrate that a targeted deletion of α-syntrophin—a member of the dystrophin complex responsible for AQP4 anchoring—removes a substantial and fairly constant proportion (79–94 %) of the perivascular AQP4 pool across the central nervous system (CNS). Quantitative immunogold analyses of AQP4 and α-syntrophin in perivascular membranes indicate that there is a fixed stoichiometry between these two molecules. Both molecules occur at higher densities in endfoot membrane domains facing pericytes than in endfoot membrane domains facing endothelial cells. Our data suggest that irrespective of region, endfoot targeting of α-syntrophin is the single most important factor determining the size of the perivascular AQP4 pool and hence the capacity for water transport at the brain–blood interface.