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Journal of Lipid Research Jun 2023Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the...
Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.
Topics: Animals; Mice; Apolipoprotein E4; Diet; Dietary Supplements; Docosahexaenoic Acids; Entorhinal Cortex; Fatty Acids, Unsaturated
PubMed: 36958720
DOI: 10.1016/j.jlr.2023.100354 -
NeuroImage Apr 2022Risk-taking differs between humans, and is associated with the personality measures of impulsivity and sensation-seeking. To analyse the brain systems involved,...
Risk-taking differs between humans, and is associated with the personality measures of impulsivity and sensation-seeking. To analyse the brain systems involved, self-report risk-taking, resting state functional connectivity, and related behavioral measures were analyzed in 18,740 participants of both sexes from the UK Biobank. Functional connectivities of the medial orbitofrontal cortex, ventromedial prefrontal cortex (VMPFC), and the parahippocampal areas were significantly higher in the risk-taking group (p < 0.001, FDR corrected). The risk-taking measure was validated in that it was significantly associated with alcohol drinking amount (r = 0.08, p = 5.1×10), cannabis use (r = 0.12, p = 6.0×10), and anxious feelings (r = -0.12, p = 7.6×). The functional connectivity findings were cross-validated in two independent datasets. The higher functional connectivity of the medial orbitofrontal cortex and VMPFC included higher connectivity with the anterior cingulate cortex, which provides a route for these reward-related regions to have a greater influence on action in risk-taking individuals. In conclusion, the medial orbitofrontal cortex, which is involved in reward value and pleasure, was found to be related to risk-taking, which is associated with impulsivity. An implication is that risk-taking is driven by specific orbitofrontal cortex reward systems, and is different for different rewards which are represented differently in the brains of different individuals. This is an advance in understanding the bases and mechanisms of risk-taking in humans, given that the orbitofrontal cortex, VMPFC and anterior cingulate cortex are highly developed in humans, and that risk-taking can be reported in humans.
Topics: Adult; Aged; Connectome; Female; Gyrus Cinguli; Humans; Impulsive Behavior; Magnetic Resonance Imaging; Male; Middle Aged; Parahippocampal Gyrus; Prefrontal Cortex; Reward; Risk-Taking
PubMed: 35007715
DOI: 10.1016/j.neuroimage.2022.118893 -
Journal of Alzheimer's Disease : JAD 2020Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are...
BACKGROUND
Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD.
OBJECTIVE
To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD.
METHODS
Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests.
RESULTS
The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA.
CONCLUSION
Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.
Topics: Aged; Alzheimer Disease; Aniline Compounds; Atrophy; CA1 Region, Hippocampal; CA2 Region, Hippocampal; CA3 Region, Hippocampal; Case-Control Studies; Dentate Gyrus; Female; Hippocampus; Humans; Image Interpretation, Computer-Assisted; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Parahippocampal Gyrus; Positron-Emission Tomography; Thiazoles
PubMed: 33074228
DOI: 10.3233/JAD-200625 -
Neuron Mar 2021Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are...
Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.
Topics: Adolescent; Adult; Animals; Auditory Cortex; Brain Mapping; Electric Stimulation; Female; Frontal Lobe; Humans; Macaca mulatta; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Parahippocampal Gyrus; Prefrontal Cortex; Species Specificity; Temporal Lobe; Young Adult
PubMed: 33482086
DOI: 10.1016/j.neuron.2020.12.026 -
Journal of Neuroinflammation Aug 2023Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and...
Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.
Topics: Animals; Mice; Lipopolysaccharides; Neuroinflammatory Diseases; Antidepressive Agents; Connexins; Entorhinal Cortex
PubMed: 37599352
DOI: 10.1186/s12974-023-02873-z -
The Journal of Neuroscience : the... Nov 2019The parahippocampal region is thought to be critical for memory and spatial navigation. Within this region lies the parasubiculum, a small structure that exhibits strong...
The parahippocampal region is thought to be critical for memory and spatial navigation. Within this region lies the parasubiculum, a small structure that exhibits strong theta modulation, contains functionally specialized cells, and projects to layer II of the medial entorhinal cortex (MEC). Thus, it is uniquely positioned to influence firing of spatially modulated cells in the MEC and play a key role in the internal representation of the external environment. However, the basic neuronal composition of the parasubiculum remains largely unknown, and its border with the MEC is often ambiguous. We combine electrophysiology and immunohistochemistry in adult mice (both sexes) to define first, the boundaries of the parasubiculum, and second, the major cell types found in this region. We find distinct differences in the colabeling of molecular markers between the parasubiculum and the MEC, allowing us to clearly separate the two structures. Moreover, we find distinct distribution patterns of different molecular markers within the parasubiculum, across both superficial-deep and DV axes. Using unsupervised cluster analysis, we find that neurons in the parasubiculum can be broadly separated into three clusters based on their electrophysiological properties, and that each cluster corresponds to a different molecular marker. We demonstrate that, while the parasubiculum aligns structurally to some to general cortical principals, it also shows divergent features in particular in contrast to the MEC. This work will form an important basis for future studies working to disentangle the circuitry underlying memory and spatial navigation functions of the parasubiculum. We identify the major neuron types in the parasubiculum using immunohistochemistry and electrophysiology, and determine their distribution throughout the parasubiculum. We find that the neuronal composition of the parasubiculum differs considerably compared with the neighboring medial entorhinal cortex. Both regions are involved in spatial navigation. Thus, our findings are of importance for unraveling the underlying circuitry of this process and for determining the role of the parasubiculum within this network.
Topics: Animals; Entorhinal Cortex; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neuroanatomical Tract-Tracing Techniques; Neurons; Spatial Navigation
PubMed: 31548233
DOI: 10.1523/JNEUROSCI.0796-19.2019 -
Nature Neuroscience Nov 2019Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of...
Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is biased by inputs from CA1 inhibitory neurons and the visual cortex, but lacks input from the entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target the perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. Our findings also implicate this circuitry in the formation of complex spatial representations and learning of object-place associations.
Topics: Animals; CA1 Region, Hippocampal; Entorhinal Cortex; Female; Hippocampus; Learning; Male; Mice; Mice, Transgenic; Neural Pathways; Neurons; Perirhinal Cortex; Space Perception; Visual Cortex
PubMed: 31548723
DOI: 10.1038/s41593-019-0496-y -
NeuroImage Sep 2021Humans use different spatial reference frames (allocentric or egocentric) to navigate successfully toward their destination in different spatial scale spaces... (Review)
Review
Humans use different spatial reference frames (allocentric or egocentric) to navigate successfully toward their destination in different spatial scale spaces (environmental or vista). However, it remains unclear how the brain represents different spatial scales and different spatial reference frames. Thus, we conducted an activation likelihood estimation (ALE) meta-analysis of 47 fMRI articles involving human spatial navigation. We found that both the environmental and vista spaces activated the parahippocampal place area (PPA), retrosplenial complex (RSC), and occipital place area in the right hemisphere. The environmental space showed stronger activation than the vista space in the occipital and frontal regions. No brain region exhibited stronger activation for the vista than the environmental space. The allocentric and egocentric reference frames activated the bilateral PPA and right RSC. The allocentric frame showed more stronger activations than the egocentric frame in the right culmen, left middle frontal gyrus, and precuneus. No brain region displayed stronger activation for the egocentric than the allocentric navigation. Our findings suggest that navigation in different spatial scale spaces can evoke specific and common brain regions, and that the brain regions representing spatial reference frames are not absolutely separated.
Topics: Environment; Humans; Nerve Net; Occipital Lobe; Parahippocampal Gyrus; Space Perception; Spatial Navigation
PubMed: 34129948
DOI: 10.1016/j.neuroimage.2021.118264 -
The Journal of Neuroscience : the... Jun 2021The postrhinal area (POR) is a known center for integrating spatial with nonspatial visual information and a possible hub for influencing landmark navigation by...
The postrhinal area (POR) is a known center for integrating spatial with nonspatial visual information and a possible hub for influencing landmark navigation by affective input from the amygdala. This may involve specific circuits within muscarinic acetylcholine receptor 2 (M2)-positive (M2) or M2 modules of POR that associate inputs from the thalamus, cortex, and amygdala, and send outputs to the entorhinal cortex. Using anterograde and retrograde labeling with conventional and viral tracers in male and female mice, we found that all higher visual areas of the ventral cortical stream project to the amygdala, while such inputs are absent from primary visual cortex and dorsal stream areas. Unexpectedly for the presumed salt-and-pepper organization of mouse extrastriate cortex, tracing results show that inputs from the dorsal lateral geniculate nucleus and lateral posterior nucleus were spatially clustered in layer 1 (L1) and overlapped with M2 patches of POR. In contrast, input from the amygdala to L1 of POR terminated in M2 interpatches. Importantly, the amygdalocortical input to M2 interpatches in L1 overlapped preferentially with spatially clustered apical dendrites of POR neurons projecting to amygdala and entorhinal area lateral, medial (ENTm). The results suggest that subnetworks in POR, used to build spatial maps for navigation, do not receive direct thalamocortical M2 patch-targeting inputs. Instead, they involve local networks of M2 interpatches, which are influenced by affective information from the amygdala and project to ENTm, whose cells respond to visual landmark cues for navigation. A central purpose of visual object recognition is identifying the salience of objects and approaching or avoiding them. However, it is not currently known how the visual cortex integrates the multiple streams of information, including affective and navigational cues, which are required to accomplish this task. We find that in a higher visual area, the postrhinal cortex, the cortical sheet is divided into interdigitating modules receiving distinct inputs from visual and emotion-related sources. One of these modules is preferentially connected with the amygdala and provides outputs to entorhinal cortex, constituting a processing stream that may assign emotional salience to objects and landmarks for the guidance of goal-directed navigation.
Topics: Amygdala; Animals; Entorhinal Cortex; Female; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Spatial Navigation; Visual Cortex
PubMed: 33849948
DOI: 10.1523/JNEUROSCI.2185-20.2021 -
Annals of Clinical and Translational... May 2020To assess the relationships between MRI volumetry and [ F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by...
OBJECTIVE
To assess the relationships between MRI volumetry and [ F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by decade).
METHODS
Five-hundred and sixty-four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer's dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and C-PiB; all 166 Alzheimer's participants were beta-amyloid positive and all controls were beta-amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal-to-neocortical and entorhinal-to-neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50-59, 60-69, and 70+). Voxel-level analyses were also performed.
RESULTS
For 50-59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel-level analysis. For 60-69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60-69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes.
INTERPRETATION
MRI volumetry versus flortaucipir PET relationships differ across Alzheimer's clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta-amyloid and tau-positive biomarker defined Alzheimer's disease.
Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Carbolines; Contrast Media; Entorhinal Cortex; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Phenotype; Positron-Emission Tomography; tau Proteins
PubMed: 32293805
DOI: 10.1002/acn3.51038