Hippocampal Responses Research Articles

An ex vivo model of systemically-mediated effects of ozone inhalation on the brain.

Air pollution is associated with increased risk of neurodegenerative and neuropsychiatric conditions. While animal models have increased our understanding of how air pollution contributes to brain pathologies - including through oxidative stress, inflammatory, and stress hormone pathways - investigation of underlying mechanisms remains limited due to a lack of human-relevant models that incorporate systemic processes. Our objective was to establish an ex vivo approach that enables assessment of the roles of plasma mediators in pollutant-induced effects in the brain. As a proof-of-concept for application in the human context, we assessed whether such effects reproduced in vivo responses to pollutant exposure. Primary rat hippocampal neurons and microglia were each treated with plasma collected from rats immediately or 24h after ozone inhalation (0 or 0.8 ppm) ± pre-treatment with the glucocorticoid synthesis inhibitor metyrapone. Microglia were further challenged with lipopolysaccharide to evaluate modification of inflammatory responses. Plasma from the ozone-exposed group produced transcriptional changes (inflammatory, antioxidant, glucocorticoid-responsive) in neurons, some of which were glucocorticoid-dependent. Ex vivo and hippocampal responses were strongly correlated, establishing the in vivo relevance of the model. Plasma from the ozone-exposed group modified inflammatory responses to lipopolysaccharide challenge in microglia, demonstrating the model's utility to assess functional changes resulting from pollutant exposure. This study establishes that an ex vivo approach can reproduce ozone-induced effects in the brain. The model was sensitive to specific plasma mediators and temporal effects, and enabled assessment of functional responses. This approach may serve to investigate mechanisms underlying effects of pollutants on the human brain.

Transcriptomics study of hippocampus in mice exposed to heat stress.

Heat stress (HS) triggers various pathophysiological responses in the brain, including neuroinflammation and cognitive impairments. The objective of this study was to examine the impact of HS by comparing the hippocampal transcriptomes of mice exposed to HS with those under control conditions. Our analysis revealed that HS exposure did not affect the number of SNP or InDel mutations in the mouse hippocampus, nor did it influence SNP functions, distribution, or types. However, HS did lead to differential gene expression in the hippocampus, with 210 differentially expressed genes (DEGs), including 72 upregulated and 138 downregulated genes. Gene Ontology (GO) analysis indicated that these DEGs are involved in hippocampal responses to various stimuli (chemical, oxygen-containing compounds, peptide hormones), metabolic processes (arachidonic acid, olefinic compound metabolism, lipid metabolism), and other functions. The regulation of these functions may be closely linked to specific DEGs, such as Card14, Ntrk1, Lcn2, Irs4, Cyp2c70, Hamp, Ambp, Gh, Mup19, and others, which exhibit the highest degree of differential variation. Furthermore, we observed that pre-treatment with taurine primarily modulated cognitive functions in the hippocampus following HS. Therefore, our study offers valuable insights for future research on heat stress-induced cognitive impairments and provides a theoretical foundation for developing taurine-based preventive strategies for high-risk populations.

Corrigendum to ‘Dexmedetomidine reduces hippocampal microglia inflammatory response induced by surgical injury through inhibiting NLRP3’ [Chinese Journal of Traumatology 22 (2019) 161-165

Corrigendum to ‘Dexmedetomidine reduces hippocampal microglia inflammatory response induced by surgical injury through inhibiting NLRP3’ [Chinese Journal of Traumatology 22 (2019) 161-165

Sex differences in insulin induced hippocampus functional connectivity during visual food cue presentation.

Central insulin has been shown to regulate eating behavior and cognitive processes in a sex-specific manner. Besides memory, the hippocampus is pivotal in the control of appetite. However, how insulin interacts with the hippocampal food cue response and the role of sex hormones in this context remain unclear. Using fMRI, we evaluated task-based functional connectivity (FC) of the hippocampus during food cue presentation in 60 participants (age: 21-69; 30 women) after intranasal insulin or placebo administration, in a randomized within-subject design. In an exploratory analysis, we investigated whether hippocampal FC after intranasal insulin administration is related to estradiol and progesterone levels during the follicular and luteal phase of the menstrual cycle in 13 premenopausal women (age: 20-28). Intranasal insulin increased hippocampal FC with the prefrontal cortex compared to placebo, regardless of sex. This correlated with stronger reduction in subjective feeling of hunger and food craving. Moreover, we observed an interaction between sex and nasal spray condition with higher hippocampal FC to the calcarine gyrus after insulin compared to placebo in men, while women showed a lower response. In premenopausal women, the centrally mediated effect of insulin on hippocampus to calcarine gyrus FC negatively correlated with the estradiol/progesterone ratio in the luteal phase. Central insulin influences hippocampal FC to regions vital for inhibitory control during high-caloric food cue presentation, implying a potential role of the hippocampal network in modulating insulin's anorexic effects. The observed sex differences between the hippocampus and visual cortex might be influenced by sex hormone action.

Association between loneliness and hippocampal responses to dynamic social stimuli in psychotic disorders.

The incidence of loneliness has increased over the past several decades worldwide and is particularly common among people with serious mental illnesses. However, this public health problem has been difficult to address, in part because the neurocognitive mechanisms underlying loneliness are poorly understood. To investigate these mechanisms, a functional magnetic resonance imaging (fMRI) study was conducted which accounted for known cognitive biases associated with loneliness. Participants with (n = 40) and without (n = 60) psychotic disorders (PD) viewed images of faces that appeared to approach or withdraw from the participants, while fMRI data were collected. Following the scanning, participants rated the trustworthiness of the faces, and these ratings were included as weights in the fMRI analyses. Neural responses to approaching versus withdrawing faces were measured, and whole brain regression analyses, with loneliness as the regressor, were performed. In the PD and full samples, a higher level of loneliness was significantly associated with greater responses of the hippocampus and areas of the basal ganglia to withdrawing (versus approaching) face stimuli. Moreover, the effects in the hippocampus, but not the basal ganglia, remained significant after controlling for potential confounds such as social activity levels, depression and social anhedonia. Lastly, in a subset of the sample (n = 66), greater hippocampal responses to withdrawing faces predicted greater loneliness one year later. Heightened responses of the hippocampus to withdrawing faces may represent a candidate objective marker of loneliness that could be modified by interventions targeting loneliness.

Understanding the Antidepressant Mechanisms of Acupuncture: Targeting Hippocampal Neuroinflammation, Oxidative Stress, Neuroplasticity, and Apoptosis in CUMS Rats.

Depression is recognized globally as one of the most intractable diseases, and its complexity and diversity make treatment extremely challenging. Acupuncture has demonstrated beneficial effects in various psychiatric disorders. However, the underlying mechanisms of acupuncture's antidepressant action, particularly in depression, remain elusive. Therefore, this study aimed to investigate the effects of acupuncture on chronic unpredictability stress (CUMS)-induced depressive symptoms in rats and to further elucidate its underlying molecular mechanisms. All rats were exposed to CUMS of two stressors every day for 28 days, except for the control group. One hour before CUMS, rats were given a treatment with acupuncture, electroacupuncture, sham-acupuncture, or fluoxetine (2.1 mg/kg). Behavioral tests and biological detection methods were conducted in sequence to evaluate depression-like phenotype in rats. The findings of this study demonstrate that acupuncture therapy effectively ameliorated depression-like behavior induced by CUMS in rats. Additionally, acupuncture exerted a restorative effect on the alterations induced by CUMS in the levels of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), cyclic AMP response element-binding protein (CREB), postsynaptic density95 (PSD95), gamma-aminobutyric acid (GABA), and acetylcholine (ACh). Additionally, our findings indicate that acupuncture also modulates the ERK and Caspase-3 apoptotic pathways in the hippocampus of CUMS rats. This study suggests that acupuncture may play a potential preventive role by regulating hippocampal neuroinflammatory response, levels of oxidative stress, apoptotic processes, and enhancing synaptic plasticity.

Role of surgical trauma in the hippocampal dopaminergic system response in simulated surgical interventions on the nasal cavity, paranasal sinuses, and alveolar process of the maxilla in rats

Aim of the study: to evaluate the impact of surgical trauma on the hippocampal dopaminergic system response in simulated surgical interventions on the nasal cavity, paranasal sinuses, and alveolar process of the maxilla in rats. Material and methods. Surgery simulation was performed on male Wistar rats under general anesthesia with Zoletil 100 solution. Septoplasty was simulated in group 1 (n=10). Dental implantation was performed in group 2 (n=10). In group 3 (n=10), a cavity was created in the alveolar process of the maxilla. In group 4, 10 rats underwent sinus lift surgery with dental implantation. In group 5 (n=10), maxillary sinusotomy was performed with injury to the mucosa of the ipsilateral maxillary sinus. Liquid chromatography with electrochemical detection was used to determine the concentration of dopamine (DA), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) in the hippocampal formation. The DOPAC/DA, HVA/DA, 3-MT/DA ratios were also determined. The control group included 10 intact rats of the same lineage. Results. The DA concentration in the hippocampus was significantly higher in group 5 and lower in group 4 compared with the control. HVA concentration was significantly higher in group 2, in group 5 (p<0.01) and in group 1 (p<0.05). Inter-group comparison revealed that HVA concentration was significantly higher in group 2 compared with the rest of the experimental groups (p<0.001). This parameter was significantly lower in groups 1, 3, and 4 compared with group 5 (p<0.01). DOPAC level was significantly higher in group 5 (p<0.01) compared with the control data. 3-MT concentration was significantly higher in groups 4 and 5 (p<0.001), as well as in groups 1 (p<0.05) and 3 (p<0.01). DOPAC/DA was significantly lower in groups 2 and 4 compared with controls (p<0.001), which was also observed in group 5 (p<0.01). HVA/DA ratio was significantly lower in groups 4 and 5 compared with the control animals (p<0.001). The 3-MT/DA ratio was significantly lower in groups 2 and 5 (p<0.01) as well as in group 4 (p<0.001) compared with the control group. Conclusion. The concentration of dopamine metabolites 3-MT, HVA, and DOPAC increases, while the dopaminergic activity of the hippocampal formation decreases in simulated sinus lift surgery with simultaneous implantation and dental implantation complicated by maxillary sinusotomy compared with the parameters in simulated septoplasty and simple maxillary alveolar process injury. Surgical trauma during the simulated operations on the nasal cavity, paranasal sinuses, and alveolar process of the maxilla in rats provokes a pronounced stress response of the hippocampal dopaminergic system, which can be interpreted as disruption of adaptive mechanisms and the development of maladaptation in the early postoperative period. Цель: оценить влияние хирургической травмы на ответ дофаминергической системы гиппокампа при моделировании хирургических вмешательств в полости носа, околоносовых пазухах и альвеолярном отростке верхней челюсти у крыс. Материал и методы. Моделирование операций проводилось на крысах-самцах линии Wistar под общей анестезией раствором Золетил 100. В 1-й группе (n=10) проводили моделирование септопластики. Во 2-й группе (n=10) проводили дентальную имплантацию. В 3-й группе (n=10) в альвеолярном отростке верхней челюсти делали лунку. В 4-й группе 10 крысам проводили синус-лифтинг с дентальной имплантацией. В 5-й группе (n=10) проводили гайморотомию с повреждением слизистой оболочки ипсилатеральной верхне- челюстной пазухи. При помощи жидкостной хроматографии с электрохимической детекцией определяли концентрацию в гиппокамповой формации дофамина (DA), гомованилиновой кислоты (HVA), 3,4-дигидрок- сифенилуксусной кислоты (DOPAC), 3-метокситирамина (3-МТ). Определяли также DOPAC/DA, HVA/DA, 3-MT/DA. Контролем являлись 10 интактных крыс той же линии. Результаты. Концентрация DA в гиппокампе по сравнению с контролем была достоверно выше в 5-й группе и ниже в 4-й группе. Концентрация HVA была значимо выше во 2-й группе, в 5-й (p<0,01) и 1-й (p<0,05) группах. Межгрупповое сравнение выявило, что концентрация HVA была значимо выше во 2-й группе по сравнению с остальными экспериментальными группами (p<0,001). В группах 1, 3 и 4 этот показатель был значимо ниже по сравнению с 5-й группой (p<0,01). Уровень DOPAC был значимо выше в 5-й группе (p<0,01) по сравнению с контрольными данными. Концентрация 3-МТ была достоверно выше в 4-й и 5-й группах (p<0,001), а также в 1-й (p<0,05) и 3-й (p<0,01) группах. DOPAC/DA было значимо ниже во 2-й и 4-й группах по сравнению с контр- олем (p<0,001), а также это отмечалось в 5-й группе (p<0,01). Отношение HVA/DA по сравнению с контрольной группой животных было достоверно ниже в группах 4 и 5 (p<0,001). Во 2-й и 5-й группах (p<0,01), а также в группе 4 (p<0,001) отношение 3-MT/DA было статистически ниже, чем у контрольной группе. Заключение. При проведении моделирования синус-лифтинга с одномоментной имплантацией и дентальной имплантации, осложненной гайморотомией, отмечается рост концентрации метаболитов DA 3-MT, HVA и DOPAC при одновременном снижении дофаминергической активности гиппокампальной формации по сравнению с моделированием септопластики и простым повреждением альвеолярного отростка верхней челюсти. Хирургическая травма при моделировании операций в полости носа, околоносовых пазухах и альвеолярном отростке верхней челюсти у крыс провоцирует выраженный стрессорный ответ дофаминергической системы гиппокампа, что можно интерпретировать как срыв адаптационных механизмов и развитие дезадаптации в раннем послеоперационном периоде.

Sex-Specific Effects of Early Life Unpredictability on Hippocampal and Amygdala Responses to Novelty in Adolescents.

Unpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala. Participants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes. Exposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally. Exposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.

Social odors drive hippocampal CA2 place cell responses to social stimuli.

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

Pleiotrophin modulates acute and long-term LPS-induced neuroinflammatory responses and hippocampal neurogenesis

The hippocampus is one of the most vulnerable regions affected in disorders characterized by overt neuroinflammation such as neurodegenerative diseases. Pleiotrophin (PTN) is a neurotrophic factor that modulates acute neuroinflammation in different contexts. PTN is found highly upregulated in the brain in different chronic disorders characterized by neuroinflammation, suggesting an important role in the modulation of sustained neuroinflammation. To test this hypothesis, we studied the acute and long-term effects of a single lipopolysaccharide (LPS; 5 mg/kg) administration in Ptn+/+ and Ptn-/- mice, and in mice with Ptn-overexpression (Ptn-Tg). Endogenous PTN levels proportionally modulate LPS-induced increase in TNF-α plasma levels one hour after treatment. In the dentate gyrus (DG) of the hippocampus, a lower percentage of DCX+ cells were detected in saline-treated Ptn-/- mice compared to Ptn+/+ mice, suggesting a crucial role of PTN in the maintenance of hippocampal neuronal progenitors. The data show that PTN overexpression tends to potentiate acute microglial responses in the DG 16 hours after LPS treatment. Remarkably, a significant increase in the number of neuronal progenitors together with astrogliosis was detected 10 months after a single injection of LPS treatment in wild type mice. However, these LPS-induced long-term effects were prevented in Ptn-/- and Ptn-Tg mice, suggesting that PTN modulates LPS-induced long-term neurogenesis changes and astrocytic response in the hippocampus. The data presented here suggest that endogenous PTN levels are crucial in the regulation of acute LPS-induced systemic and hippocampal microglial responses in young mice. Furthermore, our findings provide evidence of the key role of PTN in the regulation of long-term LPS effects on astrocytic response and neurogenesis in the hippocampus.

Empagliflozin-activated AMPK elicits neuroprotective properties in reserpine-induced depression via regulating dynamics of hippocampal autophagy/inflammation and PKCζ-mediated neurogenesis

RationaleMajor depression has been an area of extensive research during the last decades, for it represents a leading cause of disability and suicide. The stark rise of depression rates influenced by life stressors, economic threats, pandemic era, and resistance to classical treatments, has made the disorder rather challenging. Adult hippocampal neurogenesis and plasticity are particularly sensitive to the dynamic interplay between autophagy and inflammation. In fact, the intricate balance between the two processes contributes to neuronal homeostasis and survival.ObjectivesHaving demonstrated promising potentials in AMPK activation, a major metabolic sensor and autophagy regulator, empagliflozin (Empa) was investigated for possible antidepressant properties in the reserpine rat model of depression.ResultsWhile the reserpine protocol elicited behavioral, biochemical, and histopathological changes relevant to depression, Empa outstandingly hindered these pathological perturbations. Importantly, hippocampal autophagic response markedly declined with reserpine which disrupted the AMPK/mTOR/Beclin1/LC3B machinery and, conversely, neuro-inflammation prevailed under the influence of the NLRP3 inflammasome together with oxidative/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKCζ/NF-κB/BDNF/CREB signal restriction. Empa restored hippocampal monoamines and autophagy/inflammation balance, driven by AMPK activation. By promoting the atypical PKCζ phosphorylation (Thr403) which subsequently phosphorylates NF-κB at Ser311, AMPK successfully reinforced BDNF/CREB signal and hippocampal neuroplasticity. The latter finding was supported by hippocampal CA3 toluidine blue staining to reveal intact neurons.ConclusionThe current study highlights an interesting role for Empa as a regulator of autophagic and inflammatory responses in the pathology of depression. The study also pinpoints an unusual contribution for NF-κB in neurotrophins secretion via AMPK/PKCζ/NF-κB/BDNF/CREB signal transduction. Accordingly, Empa can have special benefits in diabetic patients with depressive symptoms.LimitationsThe influence of p-NF-κB (Ser311) on NLRP3 inflammasome assembly and activation has not been investigated, which can represent an interesting point for further research.Graphical abstract

Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI.

Electrical neurostimulation is currently used to manage epilepsy, but the most effective approach for minimizing seizure occurrence is uncertain. While functional MRI (fMRI) can reveal which brain areas are affected by stimulation, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. In this study, we utilized the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy (mTLE) to systematically examine the brain-wide responses to electrical stimulation using fMRI. We compared fMRI responses of saline-injected controls and epileptic mice during stimulation in the septal hippocampus (HC) at 10 Hz and demonstrated the effects of different stimulation amplitudes (80-230 μA) and frequencies (1-100 Hz) in epileptic mice. Motivated by recent studies exploring 1 Hz stimulation to prevent epileptic seizures, we furthermore investigated the effect of prolonged 1 Hz stimulation with fMRI. Compared to sham controls, epileptic mice showed less propagation to the contralateral HC, but significantly stronger responses in the ipsilateral HC and a wider spread to the entorhinal cortex and septal region. Varying the stimulation amplitude had little effect on the resulting activation patterns, whereas the stimulation frequency represented the key parameter and determined whether the induced activation remained local or spread from the hippocampal formation into cortical areas. Prolonged stimulation of epileptic mice at 1 Hz caused a slight reduction in local excitability. In this way, our study contributes to a better understanding of these stimulation paradigms.

RAGE mediates hippocampal pericyte responses and neurovascular unit lesions after TBI

Traumatic brain injury impairs brain function through various mechanisms. Recent studies have shown that alterations in pericytes in various diseases affect neurovascular function, but the effects of TBI on hippocampal pericytes remain unclear. Here, we investigated the effects of RAGE activation on pericytes after TBI using male C57BL/6 J mice. Hippocampal samples were collected at different time points within 7 days after TBI, the expression of PDGFR-β, NG2 and the HMGB1-S100B/RAGE signaling pathway was assessed by Western blotting, and the integrity of the hippocampal BBB at different time points was measured by immunofluorescence. RAGE-associated BBB damage in hippocampal pericytes occurred early after cortical impact. By culturing primary mouse brain microvascular pericytes, we determined the different effects of HMGB1-S100B on pericyte RAGE. To investigate whether RAGE blockade could protect neurological function after TBI, we reproduced the process of CCI by administering FPS-ZM1 to RAGE−/− mice. TEM images and BBB damage-related assays showed that inhibition of RAGE resulted in a significant improvement in the number of hippocampal vascular basement membranes and tight junctions and a reduction in perivascular oedema compared with those in the untreated group. In contrast, mouse behavioural testing and doublecortin staining indicated that targeting the HMGB1-S100B/RAGE axis after CCI could protect neurological function by reducing pericyte-associated BBB damage. In conclusion, the present study provides experimental evidence for the strong correlation between the pericyte HMGB1-S100B/RAGE axis and NVU damage in the hippocampus at the early stage of TBI and further demonstrates that pericyte RAGE serves as an important target for the protection of neurological function after TBI.

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

BackgroundTraumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions.MethodsWe designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche.ResultsThe data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality.ConclusionsThese data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

Experience of exercising in a noisy environment disrupts hippocampal biochemical responses to light intensity exercise

Experience of exercising in a noisy environment disrupts hippocampal biochemical responses to light intensity exercise

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.

Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD+MISO. Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4h on gestational day (GD) 14. Dams were then subjected to SD for 6h (12:00-18:00h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

Hippocampal Serotonin and Responses to Immobilization Stress in Rats Treated with Metformin

Background: Stress-related illnesses and depression are rising in modern society. Selective serotonin reuptake inhibitors as well as other antidepressants, are also not very effective and commonly exhibit partial remission, suggesting the need for novel therapeutic agents for treating anxiety and depression. Objective: The present study was designed to investigate serotonergic mechanisms in the potential anxiolytic and stress-reducing effects of metformin. Method: In the first experiment, rats were given two doses (50 and 100mg/kg) of metformin to monitor the effects of repeated administration on motor activity, anxiety, and 5-HT-1A receptor expression in the hippocampus and raphe nuclei. The second experiment was conducted in 2 parts, in 2a. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours for 5 consecutive days. Food intake and body weight were monitored daily and anxiety-like behavior was monitored on days 2 and 6. On day 6, rats were again immobilized for 2 hours, and after termination of stress rats were sacrificed to collect the hippocampus for HPLC-EC analysis of serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxy indole acetic acid (5-HIAA). In 2b. experiment, control, and metformin (50 mg/kg) treated rats were immobilized for 2 hours, and after 2 hours rats were sacrificed to collect the hippocampus for HPLC-EC analysis of 5-HT and 5-HIAA. Results: We found that metformin treatment exhibited anxiety reduction associated with greater expression of 5-HT-1A receptor in the hippocampus and reduced expression in the raphe nuclei. Immobilization stress-induced food intake and body weight deficits were comparable in control and metformin-treated rats, but the anxiogenic effects of stress were smaller in the metformintreated group. Stress-induced decreases of hippocampal 5-HT were smaller in metformin-treated than in control rats. Conclusion: Metformin can reduce stress-induced anxiety mediated via an increase in hippocampal 5-HT levels and 5-HT-1A heteroreceptor expression.

The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence.

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-β42 Accumulation.

Chronic sleep disruption (CSD), from insufficient or fragmented sleep and is an important risk factor for Alzheimer's disease (AD). Underlying mechanisms are not understood. CSD in mice results in degeneration of locus ceruleus neurons (LCn) and CA1 hippocampal neurons and increases hippocampal amyloid-β42 (Aβ42), entorhinal cortex (EC) tau phosphorylation (p-tau), and glial reactivity. LCn injury is increasingly implicated in AD pathogenesis. CSD increases NE turnover in LCn, and LCn norepinephrine (NE) metabolism activates asparagine endopeptidase (AEP), an enzyme known to cleave amyloid precursor protein (APP) and tau into neurotoxic fragments. We hypothesized that CSD would activate LCn AEP in an NE-dependent manner to induce LCn and hippocampal injury. Here, we studied LCn, hippocampal, and EC responses to CSD in mice deficient in NE [dopamine β-hydroxylase (Dbh)-/-] and control male and female mice, using a model of chronic fragmentation of sleep (CFS). Sleep was equally fragmented in Dbh -/- and control male and female mice, yet only Dbh -/- mice conferred resistance to CFS loss of LCn, LCn p-tau, and LCn AEP upregulation and activation as evidenced by an increase in AEP-cleaved APP and tau fragments. Absence of NE also prevented a CFS increase in hippocampal AEP-APP and Aβ42 but did not prevent CFS-increased AEP-tau and p-tau in the EC. Collectively, this work demonstrates AEP activation by CFS, establishes key roles for NE in both CFS degeneration of LCn neurons and CFS promotion of forebrain Aβ accumulation, and, thereby, identifies a key molecular link between CSD and specific AD neural injuries.

Divergent effects of chronic continuous and intermittent social defeat stress on emotional behaviors: Impact on phosphorylated CREB and BDNF protein levels in the rat hippocampus

Chronic psychosocial stress stands as a significant heterogeneous risk factor for psychiatric disorders. The brain’s physiological response to such stress varies based on the frequency and intensity of stress episodes. However, whether stress episodes divergently could affect hippocampal cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling remains unclear, a key regulator of psychiatric symptoms. We aimed to assess how two distinct patterns of social defeat stress exposure impact anxiety- and depression-like behaviors, fear, and hippocampal CREB-BDNF signaling in adult male rats. To explore this, adult male Sprague-Dawley rats were subjected to psychosocial stress using a Resident/Intruder paradigm for ten consecutive days (continuous social defeat stress: [CS]) or ten social defeat stress over the course of 21 days (intermittent social defeat stress [IS]). Behavioral tests (including novelty-suppressed feeding test, forced swimming test, and contextually conditioned fear) were conducted. Protein expression levels of phosphorylated CREB and BDNF in the dorsal and ventral hippocampi were examined. CS led to heightened anxiety-like behavior, fear, and increased levels of phosphorylated CREB in both the dorsal and ventral hippocampi. Conversely, IS resulted in increased anxiety-like behavior and behavioral despair alongside decreased levels of phosphorylated CREB and BDNF, particularly in the dorsal hippocampus. These findings indicate that chronic psychosocial stress divergently affects hippocampal CREB-BDNF signaling and emotional regulation depending on the stress episode. Such insights could enhance our understanding of the molecular basis of the heterogeneity of psychiatric disorders and facilitate the development of innovative treatment approaches to patients with psychiatric disorders.