Caudal Hippocampus Research Articles

Functional connectivity changes of the hippocampal subregions in anti-N-methyl-D-aspartate receptor encephalitis.

The hippocampus plays an important role in the pathophysiological mechanism of Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Nevertheless, the connection between the resting-state activity of the hippocampal subregions and neuropsychiatric disorders in patients remains unclear. This study aimed to explore the changes in functional connectivity (FC) in the hippocampal subregions of patients with anti-NMDAR encephalitis and its association with clinical symptoms and cognitive performance. Twenty-three patients with anti-NMDAR encephalitis and 23 healthy controls (HC) were recruited. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans and completed clinical cognitive scales. Based on the Brainnetome Atlas, the rostral (anterior) and caudal (posterior) hippocampi of both the left and right hemispheres were selected as regions of interest (ROIs) for FC analysis. First, a one-sample t-test was used to observe the whole-brain connectivity distribution of hippocampal subregions within the patient and HC groups at a threshold of p < 0.05. The two-sample t-test was used to compare the differences in hippocampal ROIs connectivity between groups, followed by a partial correlation analysis between the FC values of brain regions with statistical differences and clinical variables. This study observed that the distribution of whole-brain functional connectivity in the rostral and caudal hippocampi aligned with the connectivity differences between the anterior and posterior hippocampi. Compared to the HC group, the patients showed significantly decreased FC between the bilateral rostral hippocampus and the left inferior orbitofrontal gyrus and between the right rostral hippocampus and the right cerebellum. However, a significant increase in FC was observed between the right rostral hippocampus and left superior temporal gyrus, the left caudal hippocampus and right superior frontal gyrus, and the right caudal hippocampus and left gyrus rectus. Partial correlation analysis showed that FC between the left inferior orbitofrontal gyrus and the right rostral hippocampus was significantly negatively correlated with the California Verbal Learning Test (CVLT) and Brief Visuospatial Memory Test (BVMT) scores. The FC between the right rostral hippocampus and the left superior temporal gyrus was negatively correlated with BVMT scores. FC abnormalities in the hippocampal subregions of patients with anti-NMDAR encephalitis were associated with cognitive impairment, emotional changes, and seizures. These results may help explain the pathophysiological mechanisms and clinical manifestations of anti-NMDAR encephalitis and NMDAR dysfunction-related diseases such as schizophrenia.

Interaction effects between smoking and internet gaming disorder on resting-state functional connectivity of the ventral tegmental area and hippocampus.

Many reports have focused on cigarette smoking and internet gaming disorder (IGD), with widespread alterations of resting-state functional connectivity (rsFC) in the reward and memory circuits, respectively. Epidemiological studies have also shown high comorbidity of cigarette smoking and IGD. However, the underlying mechanisms are still unknown. Therefore, this study investigates the comorbidity and interaction effects between smoking and IGD from the rsFC perspective. Resting-state functional magnetic imaging data were collected from 60 healthy controls (HC), 46 smokers, 38 IGD individuals, and 34 IGD comorbid with smoking (IGDsm) participants. Voxel-wise rsFC maps were calculated for all subjects with the ventral tegmental area, rostral hippocampus, and caudal hippocampus as regions of interest, respectively. Significant interaction effects between smoking and IGD were mainly involved in the reward and memory circuits; that is, the rsFC between the ventral tegmental area and right nucleus accumbens, between the rostral hippocampus and bilateral nucleus accumbens, sensorimotor areas, and left middle temporal gyrus. Specifically, in these circuits, smokers showed decreased rsFC compared to the HC group, while IGDsm showed increased rsFC compared to smokers and IGD individuals. The IGDsm and HC groups showed no significant difference. The altered rsFC also correlated with clinical measures. These findings indicate that lower rsFC in smokers or IGD individuals increases under the effect of another type of addiction, such as smoking and IGD, but only increases to the normal state, which might explain the comorbidity and interaction between smoking and IGD from the perspective of functional circuits.

Time-series visual explainability for Alzheimer’s disease progression detection for smart healthcare

Artificial intelligence (AI)-based diagnostic systems provide less error-prone and safer support to clinicians, enhancing the medical decision-making process. This study presents a smart and reliable healthcare framework for detecting Alzheimer's disease (AD) progression. Early detection of AD before the onset of clinical symptoms is the most crucial step in starting timely treatment. To predict the conversion of cognitively normal patients to those with AD, three-dimensional (3D) magnetic resonance imaging (MRI) whole-brain neuroimaging methods have been extensively studied. However, depending on the 3D volume, this method is computationally expensive. To solve this problem, we used an approximate rank pooling method originally designed for video action recognition with a 3D MRI volume to obtain a compressed representation of multiple two-dimensional (2D) MRI slices. This study proposes a hybrid multimodal CNN-Bi-LSTM deep model for AD progression detection, in which the resulting dynamic 2D images are fused with cognitive features. Moreover, a novel explainable AI approach is proposed to provide visual explanations using the resulting longitudinal 2D dynamic images. Temporal explanations were provided by visualizing the affected brain regions captured using longitudinal 2D MRIs. By utilizing a sample of 1,692 subjects with multimodal data from the Alzheimer’s Disease Neuroimaging Initiative dataset, our method was assessed using a 10-fold cross-validation process. The model achieved an area under the receiver operating characteristics curve (AUC) of 94% using longitudinal 2D three-time-step dynamic image data. The fusion of 2D dynamic images with cognitive features enhanced the performance by 2% in terms of the AUC. Patients who gradually develop AD, show changes in various brain regions. For such patients, our system highlights the critical role of the hippocampus, medial amygdala, caudal hippocampus, and lateral amygdala at the initial time steps. In the late stages of AD, the system detects abnormalities in extra brain regions such as the medial temporal gyrus, superior temporal gyrus, fusiform gyrus, and caudal hippocampus; indicating that patients have completely progressed to AD.

Hippocampal Dynamic Functional Connectivity, HPA Axis Activity, and Personality Trait in Bipolar Disorder with Suicidal Attempt

Introduction: Suicide in bipolar disorder (BD) is a multifaceted behavior, involving specific neuroendocrine and psychological mechanisms. According to previous studies, we hypothesized that suicidal BD patients may exhibit impaired dynamic functional connectivity (dFC) variability of hippocampal subregions and hypothalamic-pituitary-adrenal (HPA) axis activity, which may be associated with suicide-related personality traits. The objective of our study was to clarify this. Methods: Resting-state functional magnetic resonance imaging data were obtained from 79 patients with BD, 39 with suicidal attempt (SA), and 40 without SA, and 35 healthy controls (HCs). The activity of the HPA axis was assessed by measuring morning plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) levels. All participants underwent personality assessment using Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Results: BD patients with SA exhibited increased dFC variability between the right caudal hippocampus and the left superior temporal gyrus (STG) when compared with non-SA BD patients and HCs. BD with SA also showed significantly lower ACTH levels in comparison with HCs, which was positively correlated with increased dFC variability between the right caudal hippocampus and the left STG. BD with SA had significantly higher scores of Hypochondriasis, Depression, and Schizophrenia than non-SA BD. Additionally, multivariable regression analysis revealed the interaction of ACTH × dFC variability between the right caudal hippocampus and the left STG independently predicted MMPI-2 score (depression evaluation) in suicidal BD patients. Conclusion: These results suggested that suicidal BD exhibited increased dFC variability of hippocampal-temporal cortex and less HPA axis hyperactivity, which may affect their personality traits.

Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD

ObjectiveThe objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. MethodsTwenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. ResultsWhole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. ConclusionCMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Functional dissociation along the rostrocaudal axis of Japanese quail hippocampus.

The mammalian hippocampus (Hp) can be functionally segregated along its septotemporal axis, with involvement of dorsal hippocampus (dHp) in spatial memory and ventral hippocampus (vHp) in stress responses and emotional behaviour. In the present study, we investigate comparable functional segregation in proposed homologues within the avian brain. Using Japanese quail (Coturnix Japonica), we report that bilateral lesions of the rostral hippocampus (rHp) produce robust deficits in a spatial Y-maze discrimination (YMD) test while sparing performance during contextual fear conditioning (CFC), comparable to results from lesions to homologous regions in mammals. In contrast, caudal hippocampus (cHp) lesions failed to produce deficits in either CFC or YMD, suggesting that, unlike mammals, both cHp and rHp of birds can support emotional behavior. These observations demonstrate functional segregation along the rostrocaudal axis of the avian Hp that is comparable in part to distinctions seen along the mammalian hippocampal septotemporal axis.

Static and dynamic functional connectivity variability of the anterior-posterior hippocampus with subjective cognitive decline

BackgroundSubjective cognitive decline (SCD) is a putative Alzheimer’s disease (AD) precursor without objective neuropsychological deficits. The hippocampus plays an important role in cognitive function and emotional responses and is generally aberrant in SCD. However, previous studies have mainly focused on static functional connectivity (sFC) by resting-state functional magnetic resonance imaging (fMRI) in SCD individuals, and it remains unclear whether hippocampal dynamic functional connectivity (dFC) changes exist in SCD and whether those changes are associated with subtle changes in cognitive function or affect.MethodsSeventy SCD patients and 65 healthy controls were recruited. Demographic data, comprehensive neuropsychology assessments, and resting-state fMRI data were collected. The bilateral anterior and posterior hippocampi were selected as seeds to investigate the static and dynamic functional connectivity alterations in SCD.ResultsCompared to healthy controls, subjects with SCD exhibited: (1) decreased sFC between the left caudal hippocampus and left precuneus; (2) decreased dFC variability between the bilateral caudal hippocampus and precuneus; (3) increased dFC variability between the bilateral rostral hippocampus and caudate nucleus; and (4) increased dFC variability between the left rostral hippocampus and left olfactory cortex. Additionally, the attention scores were positively correlated with dFC variability between the left posterior hippocampus and left precuneus, and the dFC variability between the bilateral anterior hippocampus and caudate nucleus was positively correlated with depression scores and negatively correlated with global cognition scores.ConclusionSCD individuals exhibited abnormal sFC and dFC in the anterior-posterior hippocampus, and abnormal dFC was more widespread than abnormal sFC. A combination of sFC and dFC provides a new perspective for exploring the brain pathophysiological mechanisms in SCD and offers potential neuroimaging biomarkers for the early diagnosis and intervention of AD.

Abnormal resting-state functional connectivity of hippocampal subregions in children with primary nocturnal enuresis.

ObjectivePrevious neuroimaging studies have shown abnormal brain-bladder control network in children with primary nocturnal enuresis (PNE). The hippocampus, which has long been considered to be an important nerve center for memory and emotion, has also been confirmed to be activating during micturition in several human imaging studies. However, few studies have explored hippocampus-related functional networks of PNE in children. In this study, the whole resting-state functional connectivity (RSFC) of hippocampus was investigated in children with PNE.MethodsFunctional magnetic resonance imaging data of 30 children with PNE and 29 matched healthy controls (HCs) were analyzed in our study. We used the seed-based RSFC method to evaluate the functional connectivity of hippocampal subregions defined according to the Human Brainnetome Atlas. Correlation analyses were also processed to investigate their relationship with disease duration time, bed-wetting frequency, and bladder volume.ResultsCompared with HCs, children with PNE showed abnormal RSFC of the left rostral hippocampus (rHipp) with right fusiform gyrus, right Rolandic operculum, left inferior parietal lobule, and right precentral gyrus, respectively. Moreover, decreased RSFC of the left caudal hippocampus (cHipp) with right fusiform gyrus and right supplementary motor area was discovered in the PNE group. There were no significant results in the right rHipp and cHipp seeds after multiple comparison corrections. In addition, disease duration time was negatively correlated with RSFC of the left rHipp with right Rolandic operculum (r = −0.386, p = 0.035, uncorrected) and the left cHipp with right fusiform gyrus (r = −0.483, p = 0.007, uncorrected) in the PNE group, respectively. In the Receiver Operating Characteristic (ROC) analysis, all the above results of RSFC achieved significant performance.ConclusionsTo our knowledge, this is the first attempt to examine the RSFC patterns of hippocampal subregions in children with PNE. These findings indicated that children with PNE have potential dysfunctions in the limbic network, sensorimotor network, default mode network, and frontoparietal network. These networks may become less efficient with disease duration time, inducing impairments in brain-bladder control, cognition, memory, and emotion. Further prospective research with dynamic observation of brain imaging, bladder function, cognition, memory, and emotion is warranted.

Shared and specific dynamics of brain activity and connectivity in amnestic and nonamnestic mild cognitive impairment.

The present study aimed to compare temporal variability in the spontaneous fluctuations of activity and connectivity between amnestic MCI (aMCI) and nonamnestic MCI (naMCI), which enhances the understanding of their different pathophysiologies and provides targets for individualized intervention. Sixty-five naMCI and 48 aMCI subjects and 75 healthy controls were recruited. A sliding window analysis was used to evaluate the dynamic amplitude of low-frequency fluctuations (dALFF), dynamic regional homogeneity (dReHo), and dynamic functional connectivity (dFC). The caudal/rostral hippocampus was selected as the seeds for calculating dFC. Both aMCI and naMCI exhibited abnormal dALFF, dReHo, and hippocampal dFC compared with healthy controls. Compared with individuals with naMCI, those with aMCI exhibited (1) higher dALFF variability in the right putamen, left Rolandic operculum, and right middle cingulum, (2) lower dReHo variability in the right superior parietal lobule, and (3) lower dFC variability between the hippocampus and other regions (left superior occipital gyrus, middle frontal gyrus, inferior cerebellum, precuneus, and right superior frontal gyrus). Additionally, variability in dALFF, dReHo, and hippocampal dFC exhibited different associations with cognitive scores in aMCI and naMCI patients, respectively. Finally, dReHo variability in the right superior parietal lobule and dFC variability between the right caudal hippocampus and left inferior cerebellum exhibited partially mediated effects on the different memory scores between people with aMCI and naMCI. The aMCI and naMCI patients exhibited shared and specific patterns of dynamic brain activity and connectivity. The dReHo of the superior parietal lobule and dFC of the hippocampus-cerebellum contributed to the memory heterogeneity of MCI subtypes. Analyzing the temporal variability in the spontaneous fluctuations of brain activity and connectivity provided a new perspective for exploring the different pathophysiological mechanisms in MCI subtypes.

Novel objects alter immediate early gene expression globally for ZENK and regionally for c-Fos in neophobic and non-neophobic house sparrows

Neophobia – an animal’s reluctance to approach novel objects, try new foods, or explore unfamiliar environments – affects whether animals can adapt to new environments and exploit novel resources. However, despite its importance, the neurobiological mechanisms underlying this personality trait are poorly understood. In this study, we examined regional brain activity using the expression of two immediate early genes (IEGs), ZENK and c-Fos, in response to novel objects or control conditions in captive house sparrows (Passer domesticus, n = 22). When exposed to novel objects, we predicted that we would see differential IEG activity in brain regions involved in regulating stress and emotion (hippocampus, medial ventral arcopallium, lateral septum), reward and learning (striatum), and executive function (NCL) between neophobic and non-neophobic individuals. To classify birds by phenotype, we used behavior trials that tested willingness to approach a food dish in the presence of several different novel objects, habituation to one novel object, and willingness to try several different novel foods. We then exposed birds to a new novel object or a control condition and assessed protein expression of two IEGs in neophobic vs non-neophobic individuals after this final exposure. An analysis of average sparrow feeding times in the presence of novel objects showed a bimodal distribution of neophobia behavior. There was also high repeatability of individual novel object responses, and average responses to all three trial types (novel object, novel food, and habituation to a novel object) were significantly correlated. Although we saw no differences between neophobic and non-neophobic birds in IEG expression in response to novel objects in any of the 6 brain regions examined, there was a significant global decrease in ZENK expression and a significant increase in c-Fos expression in the medial ventral arcopallium and the caudal hippocampus in response to novel objects compared to controls, suggesting that these two regions may be important in novelty detection and threat perception. Additionally, there was no object effect in the rostral hippocampus, which supports the hypothesis that the avian hippocampus may have a rostrocaudal functional gradient similar to the septotemporal gradient in mammals.

Early detection of Alzheimer's disease using 3D convolutional neural networks

AbstractBackgroundAs one of the most common neurodegenerative disorders which progress slowly over time, Alzheimer's Disease (AD) could be effectively managed by delaying the disease process through early detection and intervention at present. Mild Cognitive Impairment (MCI) is the prodromal state of AD. At present, in‐vivo structural magnetic resonance imaging (MRI) has been widely used for computer‐aided diagnosis of neurodegenerative disorders noninvasively owing to its sensitivity to morphological changes caused by brain atrophy like AD. Plus, the rapid progress of deep learning (DL), especially deep convolutional neural networks (CNNs) has improved MRI analysis thanks to its superiority in the generalization capability.MethodAn ensemble learning (EL) model which combines genetic algorithm (GA) with 3D‐CNN based on region of interest (ROI) was proposed to identify AD/MCI subjects (Figure 1). We firstly used the 3D‐CNN model to train a candidate base classifier for each a ROI (here a brain region). Then, the GA algorithm was employed to search for the best base classifier combination with the optimal generalization ability and based on it, the whole‐brain MRI classifier ensemble was built to detect AD/MCI. Owing to the one‐to‐one correspondence relationship between the base classifiers and the brain regions, we further identified those brain regions with significant classification capabilities.ResultIn three binary classification tasks, i.e., classification between 1) AD vs. NC (Normal control), 2) MCIc (MCI patients who will convert to AD) vs. NC and 3) MCIc and MCInc (MCI patients who will not convert to AD), the testing results revealed accuracy rate of 0.89±0.03, 0.88±0.03, and 0.71±0.08, with a stratified fivefold cross‐validation method, respectively. In a data‐driven way, the brain regions that greatly contributed to AD and MCI classifications (Figure 2), e.g., medial amygdala, rostral hippocampus, caudal hippocampus, were ascertained. They were linked to emotion, memory, language, and other key brain functions impaired early in the AD staging.ConclusionCompared with the 2D‐CNN models, the proposed classifiers ensemble could make full use of the effective information embedded in MRI to discover more discriminative MRI features/biomarkers. Additionally, the advocated method could also be valuable to detect the potential neuroimaging biomarkers for other brain disorders.

Cell Proliferation in the Adult Chicken Hippocampus Correlates With Individual Differences in Time Spent in Outdoor Areas and Tonic Immobility.

Access to outdoor areas is provided as a means of enhancing welfare in commercial systems for laying hens (Gallus gallus domesticus), but substantial individual differences exist in their proportional use. Baseline cell proliferation levels of Adult Hippocampal Neurogenesis (AHN) have been associated with individual differences in reactive vs. proactive coping style, and in both mammals and birds, AHN is upregulated by positive experiences including environmental enrichment and exercise. We thus sought to explore whether individual differences in use of outdoor areas and in tonic immobility responses (indicative of fearfulness) were associated with hippocampal cell proliferation and neuronal differentiation. Radio frequency identification technology was used to track the ranging behavior of 440 individual focal hens within a commercially-relevant system over a 72-days period, after which tonic immobility durations were measured. Following hippocampal tissue collection from 58 focal hens, proliferation and neuronal differentiation were measured through quantitative PCR for proliferating cell nuclear antigen (PCNA) and doublecortin mRNA, respectively. Individual differences in tonic immobility duration positively correlated with PCNA expression over the whole hippocampal formation, while greater time spent in outdoor areas (the grassy range and stone yard) was associated with higher proliferation in the rostral subregion. Basal proliferation in the chicken hippocampal formation may thus relate to reactivity, while levels in the rostral region may be stimulated by ranging experience. Doublecortin expression in the caudal hippocampus negatively co-varied with time on the grassy range, but was not associated with tonic immobility duration. This suggests that ranging outside may be associated with stress. Within laying hen flocks, individual differences in hippocampal plasticity thus relate to coping style and use of external areas.

Convergent and divergent functional connectivityalterations of hippocampal subregions between short-term and chronic insomnia disorder

Insomnia disorder (ID) is reclassified into short-term and chronic subtypes based on recent etiological advances, however, neural mechanisms underlying the subtypes are rarely examined. In this study, we investigated gray matter volume and resting-state functional connectivity (RSFC) alterations of hippocampal subregions in short-term and chronic ID using multimodal MRI. We found convergent and divergent alterations between both ID groups in specific hippocampal subregions [right cornu ammonis 1 (CA1), subicular complex (Subc), and caudal hippocampus, (cHipp)] with prefrontal cortex [bilateral medial prefrontal cortex (MPFC), and right middle frontal gyrus] and limbic/paralimbic regions (bilateral middle cingulate cortex and left parahippocampal gyrus). Intriguingly, the RSFC of the right CA1/cHipp, particularly the intersection between these two subregions, with bilateral MPFC exhibited gradual increases from healthy controls to short-term ID and from short-term ID to chronic ID. Moreover, a negative correlation between the right CA1-left parahippocampal gyrus RSFC and Epworth Sleepiness Scale scores, and a positive correlation between the right CA1-bilateral MPFC RSFC and Insomnia Severity Index scores were found in the chronic ID group (P < 0.05). Our findings suggest convergent and divergent RSFC alterations of specific hippocampal subregions with the prefrontal cortex and limbic/paralimbic regions between short-term and chronic ID. These findings suggest that the hippocampus is a key node in establishing diagnostic and categorical biomarkers in ID and developing more effective treatment strategies.

Cortisol-related hippocampal-extrastriate functional connectivity explains the adverse effect of cortisol on visuospatial retrieval

Cortisol is known to affect visuospatial memory through its major binding site in the brain, the hippocampus. The synchronization of neural activity between the hippocampus, prefrontal cortex (PFC), and visual cortex is presumed to be essential for the formation of visuospatial memory because of their visuospatial learning-dependent neuroplasticity. However, it remains unclear how hippocampal connectivity with the PFC and visual cortex is involved in the relationship between cortisol and visuospatial memory in humans. We thus investigated whether functional connectivity (FC) of the hippocampus, specifically its rostral and caudal subdivisions, mediates the relationship between visuospatial memory and endogenous cortisol. One-hundred sixty-six healthy young adults underwent standard neuropsychological tests to assess visuospatial construction (a complex figure copying test) and retrieval (the corresponding recall test) and collected their saliva at 6-time points across 2 consecutive days for measurement of daily cortisol concentrations (dCOR). Ninety of them received resting-state fMRI scans. Greater dCOR was significantly associated with better figure copying performance, but contrastingly with poorer figure recall. In proportion to dCOR, the rostral hippocampus (rHC) showed significantly increased FC with the PFC (including its dorsolateral and medial parts) and the inferior lateral occipital cortex (iLOC), while the caudal hippocampus had increased FC with the anterior middle temporal cortex. Of the cortisol-related hippocampal connectivity, the rHC-iLOC FC was specifically correlated with figure recall and showed complete mediation for the negative relationship of dCOR with figure recall. These results suggest that cortisol might have enhancing effects on visuospatial encoding as well as impairing effects on visuospatial retrieval, possibly due to its occupancy patterns of corticosteroid receptors. Cortisol’s adverse effects on visuospatial retrieval might be explained through cortisol-related rostral hippocampal connectivity with the iLOC, which is a part of the extrastriate cortex implicated in visuospatial perception. Thorough dissection of hippocampal-prefrontal-extrastriate connectivity might facilitate the understanding of neural mechanisms underlying cortisol’s contrasting effects on encoding (or consolidation) and retrieval of visuospatial information.

Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice.

Accumulation of amyloid‐β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer’s disease (AD). After almost 15 years from their generation, 3xTg‐AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg‐AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinflammation, and cognitive changes in 2‐, 6‐, 12‐, and 20‐month‐old female 3xTg‐AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had Aβ plaques in the caudal hippocampus at 6 months of age, while 100% of them had Aβ plaques in the hippocampus at 12 months of age. Cortical Aβ plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6‐month‐old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6‐month‐old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD‐like pathology in female 3xTg‐AD mice, and will facilitate the design of future studies using these mice.

Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

Repeated social defeat (RSD) is a murine stressor that models several key physiological, immunological, and behavioral alterations observed in humans exposed to psychosocial stress. RSD induces prolonged anxiety-like behavior associated with myeloid cell trafficking into the brain, including the hippocampus – a key area involved in neuroplasticity, behavior, and cognition. Therefore, the goal of this study was to investigate if the stress-induced monocyte trafficking affected hippocampal neurogenesis and cognitive function. Here, we show that RSD increased inflammatory mediators (IL1b, TNFa and IL-6) in the hippocampus, and enhanced microglia activation and monocyte trafficking (CD45hi) specifically in the caudal hippocampus. RSD also impaired spatial memory recall in the Barnes maze independent of anxiety-like behavior. RSD did not affect the number of proliferating neural progenitor cells and developing neurons when examined 14 hours post-RSD. However, there was a significant reduction in the number of young neurons and mature neurons when examined 10 days and 28 days post-RSD respectively. Consistent with region-specific neuroinflammation, reduction in the number of mature neurons was greater in the caudal hippocampus of the RSD mice compared to controls. The RSD-induced spatial deficits, which are rostral hippocampus-mediated, were resolved by 28 days. Social avoidance which is caudal hippocampus-mediated still persisted 28 days after stress. Thus, stress-induced neuroinflammation is associated with reduced neuroplasticity, and the stress-induced affective and cognitive deficits are differentially associated with hippocampal neurogenesis.

The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability.

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.

The effect of a caudal hippocampus lesion on learning in a Morris water maze in Bank Voles (Clethrionomys glareolus)

A bilateral cytotoxic lesion of the caudal hippocampus (about 1/3 of the whole hippocampus, which is insufficiently studied) influences learning of bank voles (Clethrionomys glareolus) in the Morris water maze. This effect has been estimated in this paper. A version of the test intended to measure long-term spatial memory was used. The lesion was shown to exert an influence on the learning dynamics by slowing it down, as well as to reduce the accuracy of platform location memorizing at early stages of training. The data obtained indicate the involvement of this area in control of spatial learning in rodents.

A direct morphometric comparison of five labeling protocols for multi-atlas driven automatic segmentation of the hippocampus in Alzheimer's disease

Hippocampal volumetry derived from structural MRI is increasingly used to delineate regions of interest for functional measurements, assess efficacy in therapeutic trials of Alzheimer's disease (AD) and has been endorsed by the new AD diagnostic guidelines as a radiological marker of disease progression. Unfortunately, morphological heterogeneity in AD can prevent accurate demarcation of the hippocampus. Recent developments in automated volumetry commonly use multi-template fusion driven by expert manual labels, enabling highly accurate and reproducible segmentation in disease and healthy subjects. However, there are several protocols to define the hippocampus anatomically in vivo, and the method used to generate atlases may impact automatic accuracy and sensitivity - particularly in pathologically heterogeneous samples. Here we report a fully automated segmentation technique that provides a robust platform to directly evaluate both technical and biomarker performance in AD among anatomically unique labeling protocols. For the first time we test head-to-head the performance of five common hippocampal labeling protocols for multi-atlas based segmentation, using both the Sunnybrook Longitudinal Dementia Study and the entire Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) baseline and 24-month dataset. We based these atlas libraries on the protocols of (Haller et al., 1997; Killiany et al., 1993; Malykhin et al., 2007; Pantel et al., 2000; Pruessner et al., 2000), and a single operator performed all manual tracings to generate de facto "ground truth" labels. All methods distinguished between normal elders, mild cognitive impairment (MCI), and AD in the expected directions, and showed comparable correlations with measures of episodic memory performance. Only more inclusive protocols distinguished between stable MCI and MCI-to-AD converters, and had slightly better associations with episodic memory. Moreover, we demonstrate that protocols including more posterior anatomy and dorsal white matter compartments furnish the best voxel-overlap accuracies (Dice Similarity Coefficient=0.87-0.89), compared to expert manual tracings, and achieve the smallest sample sizes required to power clinical trials in MCI and AD. The greatest distribution of errors was localized to the caudal hippocampus and the alveus-fimbria compartment when these regions were excluded. The definition of the medial body did not significantly alter accuracy among more comprehensive protocols. Voxel-overlap accuracies between automatic and manual labels were lower for the more pathologically heterogeneous Sunnybrook study in comparison to the ADNI-1 sample. Finally, accuracy among protocols appears to significantly differ the most in AD subjects compared to MCI and normal elders. Together, these results suggest that selection of a candidate protocol for fully automatic multi-template based segmentation in AD can influence both segmentation accuracy when compared to expert manual labels and performance as a biomarker in MCI and AD.

Age dependent forebrain structural changes in mice deficient in the autism associated gene Met tyrosine kinase.

The MET tyrosine kinase has been identified as a susceptibility gene in patients with autism spectrum disorders. MET is expressed in the forebrain during prenatal and postnatal development. After birth, MET participates in dendritic outgrowth and circuit formation. Alterations in neuronal development, particularly in the cerebral cortex, may contribute to the pathology of developmental disorders, including autism. Patients with autism can exhibit abnormal cortical volumes and head circumferences. We tested the hypothesis that impaired Met signaling during development alters forebrain structure. We have utilized a conditional mutant mouse line which expresses a kinase-dead Met restricted to the cerebral cortex and hippocampal structures. In these mice, we have used magnetic resonance imaging (MRI) to analyze the structure of the cerebral cortex and related structures across postnatal development. We found that the rostral cortex, caudal hippocampus, dorsal striatum, thalamus, and corpus callosum were all larger in adult, but not juvenile, mutant mice relative to control mice. The specificity of the changes suggests that aberrant expansion of the forebrain is consistent with continued axonal and dendritic growth, potentially leading to improper circuit formation and maintenance.