Hippocampal Structural Alterations Research Articles

Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

Impact of sleep disturbance in shift workers on hippocampal volume and psychomotor speed.

Shift work interferes with circadian rhythms, affecting sleep quality and cognitive function. Poor sleep quality in shift workers can impair psychomotor performance due to fatigue and sleepiness, increasing the risk of errors, accidents, and reduced productivity. Given the potential for atrophic changes in the hippocampus due to sleep disturbances, our study investigates how poor sleep quality correlates with hippocampal structural alterations and impacts psychomotor performance among shift workers. We recruited 100 shift workers, classifying them based on sleep quality into two groups: good sleep-SW group (n = 59) and poor sleep-SW group (n = 41). Sleep quality was assessed using both 7-day actigraphy for sleep efficiency and the Pittsburgh Sleep Quality Index. A control group of 106 non-shift workers without sleep problems (non-SW group) was also included for comparison. The outcome measures were psychomotor speed and hippocampal volumes, both total and by subfield. The poor sleep-SW group showed significantly smaller hippocampal volumes than both the good sleep-SW group (P<0.001) and the non-SW group (P=0.003). Longer shift work years correlated with greater reductions in hippocampal volume in this group (r=-0.42, P=0.009), unlike in the good sleep-SW group (r=0.08, P=0.541). Furthermore, they demonstrated declines in psychomotor speed relative to the non-SW group (P=0.006), which correlated with smaller hippocampal volumes (r=0.37, P=0.020). Shift workers with poor sleep quality exhibit significant hippocampal volume reductions and psychomotor speed decline, underscoring the importance of early intervention and support for sleep issues in this population.

High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Chronic Prostatitis/Chronic Pelvic Pain Syndrome Induces Depression-Like Behavior and Learning-Memory Impairment: A Possible Link with Decreased Hippocampal Neurogenesis and Astrocyte Activation.

Pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains unclear since it represents an interplay between immunological, endocrine, and neuropsychiatric factors. Patients suffering from CP/CPPS often develop mental health-related disorders such as anxiety, depression, or cognitive impairment. The aim of this study was to investigate depression-like behavior, learning, and memory processes in a rat model of CP/CPPS and to determine the alterations in hippocampal structure and function. Adult male Wistar albino rats (n = 6 in each group) from CP/CPPS (single intraprostatic injection of 3% λ-carrageenan, day 0) and Sham (0.9% NaCl) groups were subjected to pain threshold test (days 2, 3, and 7), depression-like behavior, and learning-memory tests (both on day 7). Decreased pain threshold in the scrotal region and histopathological presence of necrosis and inflammatory infiltrate in prostatic tissue confirmed the development of CP/CPPS. The forced swimming test revealed the depression-like behavior evident through increased floating time, while the modified elevated plus maze test revealed learning and memory impairment through prolonged transfer latency in the CP/CPPS group in comparison with Sham (p < 0.001 and p < 0.001, respectively). Biochemical analysis showed decreased serum levels of testosterone in CP/CPPS group vs. the Sham (p < 0.001). The CP/CPPS induced a significant upregulation of ICAM-1 in rat cortex (p < 0.05) and thalamus (p < 0.01) and increased GFAP expression in the hippocampal astrocytes (p < 0.01) vs. Sham, suggesting subsequent neuroinflammation and astrocytosis. Moreover, a significantly decreased number of DCX+ and Ki67+ neurons in the hippocampus was observed in the CP/CPPS group (p < 0.05) vs. Sham, indicating decreased neurogenesis and neuronal proliferation. Taken together, our data indicates that CP/CPPS induces depression-like behavior and cognitive declines that are at least partly mediated by neuroinflammation and decreased neurogenesis accompanied by astrocyte activation.

Glutamate released by Cajal-Retzius cells impacts specific hippocampal circuits and behaviors.

SUMMARYThe impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.

The preventive and therapeutic effect of repetitive transcranial magnetic stimulation on radiation-induced brain injury in mice

Purpose To clarify the preventive and therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on brain injury induced by X-ray cranial irradiation, preliminarily identify the mechanism and provide a novel clinical approach for the prevention and treatment of radiation-induced brain injury (RBI). Materials and methods Male C57BL/6 mice were randomly divided into the sham group, large fractionated dose (5 Gy × 4 d) group, large fractionated dose + rTMS (5 Gy × 4 d + rTMS) group, conventional fractionated dose (2 Gy × 10 d) group and conventional fractionated dose + rTMS (2 Gy × 10 d + rTMS) group. After cranial irradiation and rTMS, behavioral experiments, morphological staining and molecular biology experiments were performed. We further determined the mechanism of rTMS on the prevention and treatment of RBI, including changes in hippocampal neuronal apoptosis, neural stem cell (NSC) proliferation and differentiation, and neuronal synaptic plasticity. Results rTMS alleviated the negative effects of cranial radiation on the general health of mice and promoted their recovery. rTMS ameliorated the impairment of spatial learning and memory induced by cranial radiation, and this beneficial effect was more robust in the conventional fractionated dose group than the large fractionated dose group. Moreover, rTMS alleviated the alterations in hippocampal structure and neuronal death and had preventive and therapeutic effects against RBI. In addition, rTMS reduced hippocampal cell apoptosis, promoted NSC proliferation and differentiation in the hippocampus after cranial irradiation, and enhanced neuronal synaptic plasticity in the hippocampus. Subsequent studies showed that rTMS upregulated the expression of learning- and memory-related proteins. Conclusion rTMS could alleviate learning and memory impairment caused by RBI, and the preventive and therapeutic effects of rTMS were better for the conventional fraction radiation paradigms.

Hippocampal structural alterations in early-stage psychosis: Specificity and relationship to clinical outcomes

Hippocampal dysfunctions are a core feature of schizophrenia, but conflicting evidence exists whether volumetric and morphological changes are present in early-stage psychosis and to what extent these deficits are related to clinical trajectories. In this study, we recruited individuals at clinical high risk for psychosis (CHR-P) (n = 108), patients with a first episode of psychosis (FEP) (n = 37), healthy controls (HC) (n = 70) as well as a psychiatric control group with substance abuse and affective disorders (CHR-N: n = 38). MRI-data at baseline were obtained and volumetric as well as vertex analyses of the hippocampus were carried out. Moreover, volumetric changes were examined in the amygdala, caudate, nucleus accumbens, pallidum, putamen and thalamus. In addition, we obtained follow-up functional and symptomatic assessments in CHR-P individuals to examine the question whether anatomical deficits at baseline predicted clinical trajectories. Our results show that the hippocampus is the only structure showing significant volumetric decrease in early-stage psychosis, with FEPs showing significantly smaller hippocampal volumes bilaterally alongside widespread shape changes in the vertex analysis. For the CHR-P group, volumetric decreases were confined to the left hippocampus. However, hippocampal alterations in the CHR-P group were not robustly associated with clinical outcomes, including the persistence of attenuated psychotic symptoms and functional trajectories. Accordingly, our findings highlight that dysfunctions in hippocampal anatomy are an important feature of early-stage psychosis which may, however, not be related to clinical outcomes in CHR-P participants.

Hippocampal subregional alterations and verbal fluency in the early stage of type 2 diabetes mellitus.

Growing evidence indicates that type 2 diabetes mellitus (T2DM)-related cognitive dysfunction may develop in the early stage of the disease and is often accompanied by hippocampal structural alterations. In the current study, we investigated volume and shape alterations of the hippocampus at a subregional level in patients with T2DM. With the use of high-resolution brain structural images that were obtained from 30 T2DM patients with less than 5 years of disease duration and 30 healthy individuals, volumetric and shape analyses were performed. We also assessed the relationship between T2DM-related hippocampal structural alterations and performance on verbal fluency. In volumetric analysis, total hippocampal volume was smaller in the T2DM group, relative to the control group. At a subregional level, T2DM patients showed significant inward deformation and volume reduction of the right dentate gyrus and cornu ammonis 2/3 subregions as compared with healthy individuals. In particular, T2DM patients with lower performance on verbal fluency had smaller right dentate gyrus volumes relative to those with higher performance. These findings suggest that the hippocampus may undergo atrophy at a subregional level even in the early stage of T2DM, and this subregion-specific atrophy may be associated with reduced performance on verbal fluency.

Dietary Fructose Intake and Hippocampal Structure and Connectivity during Childhood.

In rodent literature, there is evidence that excessive fructose consumption during development has a detrimental impact on hippocampal structure and function. In this study of 103 children ages 7–11 years old, we investigated whether dietary fructose intake was related to alterations in hippocampal volume and connectivity in humans. To examine if these associations were specific to fructose or were related to dietary sugars intake in general, we explored relationships between dietary intake of added sugars and the monosaccharide, glucose, on the same brain measures. We found that increased dietary intake of fructose, measured as a percentage of total calories, was associated with both an increase in the volume of the CA2/3 subfield of the right hippocampus and increased axial, radial, and mean diffusivity in the prefrontal connections of the right cingulum. These findings are consistent with the idea that increased fructose consumption during childhood may be associated with an inflammatory process, and/or decreases or delays in myelination and/or pruning. Increased habitual consumption of glucose or added sugar in general were associated with an increased volume of right CA2/3, but not with any changes in the connectivity of the hippocampus. These findings support animal data suggesting that higher dietary intake of added sugars, particularly fructose, are associated with alterations in hippocampal structure and connectivity during childhood.

Hippocampal structural alterations and neurocognitive performance in the bipolar-schizophrenic spectrum

Hippocampal structural alterations and neurocognitive performance in the bipolar-schizophrenic spectrum

Radiation-induced hippocampal atrophy in patients with nasopharyngeal carcinoma early after radiotherapy: a longitudinal MR-based hippocampal subfield analysis.

Increasing evidence indicates that radiation-induced injury to the hippocampus may play a critical role in neurocognitive dysfunction in patients with nasopharyngeal carcinoma (NPC). However, few studies have assessed RT-induced hippocampal structural alterations in these patients early after radiotherapy (RT). In this study, 58 NPC patients were longitudinally followed up prior to treatment initiation as well as 3 and 6months after RT, respectively. Twenty comparable normal controls were recruited and followed up in parallel. A novel magnetic resonance imaging (MRI)-based automated method was used to label hippocampal subfields. The linear mixed model was employed to evaluate longitudinal changes in the volumes of the whole hippocampus and seven hippocampal subfields. Time-dependent volume reduction was observed in the bilateral hippocampus, as well as in the bilateral granule cell layer (GCL), bilateral cornu ammonis 1 (CA1), bilateral molecular layer (ML), and bilateral subiculum (SUB) in NPC patients, but not in controls. Moreover, volume deficits in the bilateral hippocampus, bilateral GCL, and right ML showed dose-dependent patterns, and high volume losses in the bilateral hippocampus, bilateral GCL, left SUB, and right ML were associated with a rapid decline in cognitive function. Our findings demonstrated that the hippocampal subfields were selectively injured by irradiation-related early neurotoxic effects, which might account for cognitive impairment in NPC patients at an early stage after RT. Further, structural MRI could serve as a potential noninvasive imaging biomarker for the early detection of radiation effects on the hippocampus in NPC patients after RT.

Evidence of Hippocampal Structural Alterations in Gulf War Veterans With Predicted Exposure to the Khamisiyah Plume.

To replicate and expand our previous findings of smaller hippocampal volumes in Gulf War (GW) veterans with predicted exposure to the Khamisiyah plume. Total hippocampal and hippocampal subfield volumes were quantified from 3 Tesla magnetic resonance images in 113 GW veterans, 62 of whom had predicted exposure as per the Department of Defense exposure models. Veterans with predicted exposure had smaller total hippocampal and CA3/dentate gyrus volumes compared with unexposed veterans, even after accounting for potentially confounding genetic and clinical variables. Among veterans with predicted exposure, memory performance was positively correlated with hippocampal volume and negatively correlated with estimated exposure levels and self-reported memory difficulties. These results replicate and extend our previous finding that low-level exposure to chemical nerve agents from the Khamisiyah pit demolition has detrimental, lasting effects on brain structure and function.

Separation increases passive stress-coping behaviors during forced swim and alters hippocampal dendritic morphology in California mice

Individuals within monogamous species form bonds that may buffer against the negative effects of stress on physiology and behavior. In some species, involuntary termination of the mother-offspring bond results in increased symptoms of negative affect in the mother, suggesting that the parent-offspring bond may be equally as important as the pair bond. To our knowledge, the extent to which affect in paternal rodents is altered by involuntary termination of the father-offspring bond is currently unknown. Here, we investigated to what extent separation and paternal experience alters passive stress-coping behaviors and dendritic morphology in hippocampal subfields of California mice (Peromyscus californicus). Irrespective of paternal experience, separated mice displayed shorter latencies to the first bout of immobility, longer durations of immobility, and more bouts of immobility than control (non-separated) mice. This effect of separation was exacerbated by paternal experience in some measures of behavioral despair—separation from offspring further decreased the latency to immobility and increased bouts of immobility. In the dentate gyrus, separation reduced dendritic spine density regardless of paternal experience. Increased spine density was observed on CA1 basal, but not apical, dendrites following paternal experience. Regardless of offspring presence, fatherhood was associated with reduced apical dendritic spine density in area CA3 of the hippocampus. Separation enhanced complexity of both basal and apical dendrites in CA1, while fatherhood reduced dendritic complexity in this region. Our data suggest that forced dissolution of the pair bond induces passive stress-coping behaviors and contributes to region-specific alterations in hippocampal structure in California mouse males.

Post-natal Deletion of Neuronal cAMP Responsive-Element Binding (CREB)-1 Promotes Pro-inflammatory Changes in the Mouse Hippocampus.

By taking advantage of a "floxed" conditional CREB mutant mouse (CREB1loxP/loxP), in which postnatal deletion of the Creb gene in the forebrain is driven by the calcium/calmodulin-dependent protein kinase II-α gene (Camk2a) promoter (BCKO mice), we here show that selective disruption of CREB function in adult forebrain neurons results, in adult mice, in morphological alterations at the hippocampal level, including hippocampal shrinkage, reduced somal volume of neurons, microgliosis and mild reactive astrocytosis, mainly involving the CA1 subfield. The huge increase of microglial cells showing a mild activated profile, and the higher percentage of double-stained GFAP/S100B astrocytes, together with the increased expression of S100b mRNA at hippocampal level, suggest the establishment of a sub-inflammatory environment in the hippocampus of BCKO mice compared with age-matched controls. Collectively, the present data link neuron-specific, adult deletion of CREB to hippocampal structural alterations and to the early appearance of neuropathological features closely resembling those occurring in the aged brain. This information may be valuable for the understanding of the role of CREB in neuroinflammatory pathways.

Multi-omics profile of the mouse dentate gyrus after kainic acid-induced status epilepticus.

Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics, and can be modeled in mice by administration of kainic acid (KA). Adult neurogenesis in the dentate gyrus (DG) contributes to hippocampal functions and has been reported to contribute to the development of TLE. Some of the phenotypical changes include neural stem and precursor cells (NPSC) apoptosis, shortly after their birth, before they produce hippocampal neurons. Here we explored these early phenotypical changes in the DG 3 days after a systemic injection of KA inducing status epilepticus (KA-SE), in mice. We performed a multi-omics experimental setup and analyzed DG tissue samples using proteomics, transcriptomics and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. We here present a description of how these data were obtained and make them available for further analysis and validation. Our data may help to further identify and characterize molecular mechanisms involved in the alterations induced shortly after KA-SE in the mouse DG.

Depression in type 2 diabetes mellitus: prevalence, impact, and treatment.

Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome.

Hippocampal Volume in Type 1 Diabetes

The hippocampus plays an important role in human memory and is known to be vulnerable to extreme hyperglycemia and hypoglycemia in animal models of type 1 diabetes. Within humans with type 1 diabetes, exposure to glycemic extremes has been associated with alterations in hippocampal structure and in memory function, but results are inconsistent. It has been hypothesized that the effects of hypoglycemia and hyperglycemia on the hippocampus may depend on when during neurodevelopment these extremes occur, possibly explaining some of these inconsistencies. However, data addressing this concept are limited. We review here the existing literature on this complex topic and suggest future avenues of required research.

Enhanced Mossy Fiber Sprouting and Synapse Formation in Organotypic Hippocampal Cultures Following Transient Domoic Acid Excitotoxicity

We have previously reported evidence of BDNF upregulation and increased neurogenesis in rat organotypic hippocampal slice cultures (OHSC) after a transient excitotoxic injury to the hippocampal CA1 area induced by low concentrations of the AMPA/kainate receptor agonist domoic acid (DOM). The changes observed in OHSC were consistent with observations in vivo, where low concentrations of DOM administered to rats during perinatal development caused increased BDNF and TrkB expression in the resulting adult animals. The in vivo low dose-DOM treatment also results in permanent alterations in hippocampal structure and function, including abnormal formation of dentate granule cell axons projecting to area CA3 (mossy fiber sprouting). Our objective in the current study is to determine if low concentrations of DOM induce mossy fiber sprouting and/or synaptogenesis in OHSC in order to facilitate future studies on the mechanisms of structural hippocampal plasticity induced by DOM. We report herein that application of a low concentration of DOM (2 μM) for 24 h followed by recovery induced a significant increase in the expression of the mossy fiber marker ZnT3 that progressed over time in culture. The DOM insult (2 μM, 24 h) also resulted in a significant upregulation of both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. All of the observed effects were fully antagonized by co-administration of the AMPA/kainate antagonists CNQX or NBQX but only partly by the NMDA antagonist CPP and not by the calcium channel blocker nifedipine. We conclude that exposure of OHSC to concentrations of DOM below those required to induce permanent neurotoxicity can induce a progressive change in hippocampal structure that can effectively model DOM effects in vivo.

Hippocampal Volume in Type 1 Diabetes

The hippocampus plays an important role in human memory and is known to be vulnerable to extreme hyperglycemia and hypoglycemia in animal models of type 1 diabetes. Within humans with type 1 diabetes, exposure to glycemic extremes has been associated with alterations in hippocampal structure and in memory function, but results are inconsistent. It has been hypothesized that the effects of hypoglycemia and hyperglycemia on the hippocampus may depend on when during neurodevelopment these extremes occur, possibly explaining some of these inconsistencies. However, data addressing this concept are limited. We review here the existing literature on this complex topic and suggest future avenues of required research.

Hippocampal Volume in Type 1 Diabetes.

The hippocampus plays an important role in human memory and is known to be vulnerable to extreme hyperglycaemia and hypoglycaemia in animal models of type 1 diabetes. Within humans with type 1 diabetes, exposure to glycaemic extremes has been associated with alterations in hippocampal structure and in memory function, but results are inconsistent. It has been hypothesised that the effects of hypoglycaemia and hyperglycaemia on the hippocampus may depend on when during neurodevelopment these extremes occur, possibly explaining some of these inconsistencies. However, data addressing this concept are limited. We review here the existing literature on this complex topic and suggest future avenues of required research.