Hippocampal Pathway Research Articles

Ascorbic acid Mitigates behavioural disturbances associated with letrozole-induced PCOS via switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in rat hippocampus

PurposePolycystic ovary syndrome (PCOS) is an endocrine disorder with the highest prevalence among other disorders in sexually-active women. It is associated with broad-spectrum hormonal and metabolic disturbances with behavioural difficulties. Experimentally, letrozole administration causes similar findings. Ascorbic acid is powerful anti-oxidant; and its cellular levels decrease with “hyperglycemic and poor anti-oxidative” status, which is, a main hallmark of PCOS. Thus, ascorbic acid administration may prevent the induction of PCOS and its consequences.Basic procedures: Forty female rats were divided into four groups (n = 10 in each): normal control (CTRL), ascorbic acid (ASC), letrozole (LTZ), and ascorbic acid + letrozole (ASC + LTZ) group. Behavioural tests (Y-maze spontaneous alteration, tail suspension test, forced swimming test) were performed. In serum, hormones (testosterone, estradiol, progesterone), glycemia (blood glucose, insulin and HOMA-IR) and oxidative stress (SOD activity, GSH) markers were measured. In hippocampus, inflammation and apoptosis indicators (p-JAK2, p-STAT5, p-ERK1/2, NF-κB, BAX, Bcl2, BAX/Bcl2 ratio) and neurotransmitters (DA, 5-HT, NE, BDNF) were determined. Lastly, ovary histopathological investigation was conducted to confirm PCOS induction.Principal results: Letrozole induced PCOS with subsequent disturbances. Testosterone levels were augmented while estradiol and progesterone were declined. Fasting blood glucose, insulin, HOMA-IR and oxidative stress markers were elevated. The expression of p-JAK2, p-STAT5, p-ERK1/2, BAX and the levels of NF-κB were increased, but Bcl2 expression, monoamines and BDNF levels were lowered. Importantly, ASC abated the last mentioned parameters markedly. Major conclusions: Ascorbic acid mitigated the behavioural difficulties of PCOS possibly by switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in hippocampus along with its neurotransmission-improving, hormonal-normalizing, anti-hyperglycemic and anti-oxidative effects.

Neuronal ACE1 knockout disrupts the hippocampal renin angiotensin system leading to memory impairment and vascular loss in normal aging

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I into angiotensin II in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression of RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA1 region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. Interestingly, ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE1 cKO mice exhibited age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE1 and cerebrovascular function in the hippocampus.

Effect of acupuncture on AMPK/ULK1 signaling pathway of hippocampus in chronic stress-induced depression rats

To observe the effect of manual acupuncture stimulation on changes of behavior and hippocampal signaling pathways of AMP-activated kinase (AMPK)/UNC-51-like kinase 1 (ULK1) in rats with chronic unpredictable mild stress (CUMS)-induced depression, so as to explore its molecular mechanism underlying improvement of depression. Thirty-two male SD rats were randomly divided into normal control, model, acupuncture and medication (fluoxetine) groups, with 8 rats in each group. The depression model was established by using CUMS (fasting, water depredation, restraint, swimming in cold water, crowding, stroboscope stimulation, and tail clipping, each of which was used once a week) for 6 weeks. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 10 min, once daily, 6 times a week for 6 weeks before every-day modeling. Rats of the medication group received gavage of fluoxetine (10 mg/kg) once a day for 6 weeks before every-day modeling. The percentage of sucrose preference, and the percentages of open arm times and open arm time in the elevated plus maze experiments were detected. The expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the hippocampus tissue were detected by Western blot, and the expression of autophagy effecting protein (Beclin-1) and the selective autophagy receptors (p62) mRNA in the hippocampal tissue was detected using real-time fluorescence quantitative PCR, respectively. Compared with the normal group, the percentage of sucrose preference, percentage of times of entering the open arm and percentage of open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1 /ULK1 ratio of proteins, and Beclin-1 mRNA were significantly decreased (P<0.01, P<0.05), and the expression levels of p-mTOR /mTOR ratio and p62 mRNA were significantly increased (P<0.01, P<0.05) in the model group. In comparison with the model group, the percentage of sucrose preference, percentage of open arm times and open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1/ULK1 ratio of proteins, and Beclin-1 mRNA were significantly increased in both acupuncture and medication groups (P<0.01, P<0.05), while the expression levels of p-mTOR /mTOR ratio of proteins, and p62 mRNA were markedly decreased only in the medication group (P<0.05). Acupuncture treatment can alleviate depression-like behavior in CUMS rats, which may be related to its functions in up-regulating AMPK/ULK1 signaling pathway to induce cellular autophagy in the hippocampus.

Electroacupuncture improves cognitive function by modulating hippocampal lactate-mediated HIF-1α signaling pathway and inhibiting inflammation response in vascular dementia rats

To observe the effects of electroacupuncture (EA) stimulation of "Sishencong"(EX-HN1) and "Fengchi"(GB20) on lactate (Lac) content, expression of proline hydroxylase 2 (PHD2), hypoxia-inducible factor-1α (HIF-1α)/nuclear transcription factor- κB (NF- κB)/NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) signaling pathway, and inflammatory factors in hippocampal tissue of vascular dementia (VD) rats, so as to explore its mechanisms underlying improvement of VD. Male SD rats screened by Morris water maze tests were randomly divided into blank control, sham-operation, VD model and EA groups (12 rats in each group). The VD model was replicated using the 4-vessel occlusion (VO) method. EA (2 Hz, 1 mA) was applied to EX-HN1 and bilateral GB20 for 30 min, once daily for consecutive 21 days. Morris water maze test was employed to test the rat's memory learning ability before and after modeling and after the intervention. The hippocampal tissue was sampled for observing histopathologic changes with H.E. staining；and detecting Lac content with colorimetric method, and the contents of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18 (also in serum) by using ELISA, respectively. The immunoactivity levels of PHD2, HIF-1α, and p-NF-κB p65 in hippocampal tissue were detected by immunohistochemistry, and the expression levels of PHD2, HIF-1α, NF-κB p65, p-NF-κB p65 and NLRP3 proteins in hippocampal tissue were detected by Western blot. Compared with the blank control and sham-operation groups, the escaping latency, Lac content in hippocampus, the TNF-α, IL-1β, and IL-18 contents in both hippocampus and serum, the immunoactivity of HIF-1α and p-NF-κB p65 and expression levels of HIF-1α, NF-κB p65, p-NF-κB p65, and NLRP3 proteins were significantly increased (P<0.01), while the number of original platform crossing, and PHD2 immunoactivity and protein expression level were significantly decreased (P<0.05, P<0.01) in the model group. Following EA intervention, modeling induced increase and decrease of the indexes mentioned above were all reversed in the EA group (P<0.05, P<0.01). H.E. staining showed disordered arrangement of neurons, uneven cytoplasm stain, blurred nucleolus or disappearance of nucleolus, dilated capillaries, many apoptotic bodies and increased inflammatory cells in the hippocampus tissue of the model group, which was improved to a certain extent in the EA group, including relatively regular arrangement of neurons, reduced apoptotic bodies and inflammatory cells, etc. in the hippocampus. EA stimulation of EX-HN1 and GB20 can improve the cognitive function in VD rats, which may be related to its functions in reducing Lac content, regulating the expression of HIF-1α pathway related proteins, and inhibiting inflammatory responses in the hippocampus tissue.

Evaluation of TRPM2 Channel-Mediated Autophagic Signaling Pathway in Hippocampus and Cortex Tissues of Rat Offspring Following Prenatal Exposure to Elevated Alcohol Levels.

Fetal alcohol syndrome (FAS) can occur because of high amount of alcohol intake during pregnancy and is characterized by both physical and neurological problems. Children diagnosed with FAS have difficulties in learning, memory, and coordination. Hippocampus has a major role in memory and learning. We aimed to determine whether alcohol exposure during pregnancy had any effect on offspring by evaluating learning ability as well as oxidative stress and autophagy in the hippocampus and cortex tissues of litters. Attention was also paid to sex differences. To do so, TRPM2, Beclin1, p62, LC3B, IBA1, parvalbumin, GAD65, and mGluR5 expression levels were evaluated by immunohistochemistry. Lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels, as well as total oxidant (TOS) and total antioxidant (TAS) status were determined by ELISA. Learning experiments were evaluated by the Morris water maze (MWM) test. Our findings demonstrated that IBA1, LC3B, GAD65, and mGluR5 expression levels were higher in female rats of the chronic alcohol exposure (CAE) model. Our IHC results revealed that TRPM2 expression levels were significantly increased in both males and females in the CAE group. Likewise, TAS was lower, and TOS was higher in CAE animals. Moreover, MWM outcomes supported a learning deficiency in CAE litters compared to controls and indicated that female offspring outperformed males in learning experiments. Therefore, our results revealed the detrimental effects of alcohol exposure during pregnancy on autophagy signaling in the hippocampus and cortex tissue of litters, which could affect the learning ability of animals.

Electroacupuncture attenuates depressive-like behaviors in poststroke depression mice through promoting hippocampal neurogenesis and inhibiting TLR4/NF-κB/NLRP3 signaling pathway.

The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24 h after MCAO for 4 weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1β, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P < 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P < 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P < 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P < 0.05) the high levels of IL-1β, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus.

Effects of treadmill exercise on endoplasmic reticulum protein folding and endoplasmic reticulum-associated protein degradation pathways in APP/PS1 mice

A hallmark of Alzheimer's disease (AD) is the disruption of protein homeostasis (proteostasis), manifested by the misfolding and aggregation of proteins. Molecular chaperones and the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway in the ER are essential for correct protein folding and degradation of misfolded proteins respectively, thus contributing to the maintenance of proteostasis. The present study aimed to investigate whether the beneficial effects of exercise in an AD mice model is associated with changes in ER protein folding and ERAD. APP/PS1 transgenic and wild-type mice were subjected to treadmill exercise for three months. The levels of molecular chaperones, specifically protein disulfide isomerases (PDIs) and heat shock proteins (HSPs), as well as ERAD-associated molecules were analyzed in the hippocampus. The result revealed a decrease in mRNA levels of PDIA2, PDIA3, PDIA4, PDIA5, PDIA6, HSPA1B, HSPA8, HSP90B1, DNAJB2, CRYAB, and CNX, an increase in mRNA levels of HSPA5 and HSPH1, an increase in protein levels of HERPUD1, and a decrease in protein levels of VCP in APP/PS1 mice. However, following a 3-month treadmill exercise regimen, an increase in mRNA levels of PDIA2, PDIA4, PDIA6, HSPA1A, HSPA8, HSP90AB1, and DNAJB2, as well as an increase in protein levels of VCP and DERL2, and a decrease in protein levels of HERPUD1 were noted. Overall, our findings indicate that disruptions in hippocampal ER protein folding and ERAD pathways may be implicated in AD, with exercise serving as a regulator of these pathways.

Vitamin D Mitigates Depression-related Disorders in an Animal Model of Depression: A Behavioral, Anatomopahtological, and Molecular Investigation, Implicating the Hippocampal BDNF Signaling Pathway

Background: Major depressive disorder represents a complicated mental disorder characterized by persistent feelings of unhappiness and loss of interest. More evidence suggests a high potential correlation between vitamin D deficiency and depression. However, the underlying mechanisms and the therapeutic potential of vitamin D supplementation are still not properly understood. The purpose of this research is to evaluate the effect of vitamin D supplementation on depressive behaviors using a rat model of depression and explore the potential mechanisms involved. Depression is a prevalent mental health disorder that significantly impacts the quality of life of individuals. Despite the availability of various treatment options, many patients still experience suboptimal outcomes, highlighting the need for further exploration of novel therapeutic approaches. In recent years, the importance of vitamin D in mental health, particularly in depression, has gained considerable attention. Methods: In this project, we propose to utilize an animal model of depressed rats to evaluate the effect of vitamin D supplementation on depressive behaviors. We employed a range of well-established behavioral tests to assess changes in depressive-like behaviors following vitamin D supplementation. Additionally, histopathological examinations of the hippocampal region, known to be involved in mood regulation, were performed to assess structural alterations and cellular changes associated with depression and vitamin D supplementation. Results: The findings demonstrate the therapeutic potential of vitamin D supplementation by improving neuronal reorganization and proliferation in the hippocampus, suggesting an interest in investigating other mechanisms of interaction. Conclusion: The findings of this research will provide valuable insight into the therapeutic potential of vitamin D in depression and shed light on the underlying mechanisms involved.

Ngfr+ cholinergic projection from SI/nBM to mPFC selectively regulates temporal order recognition memory

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr−/− mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr−/− SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr−/− mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr−/− mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.

The Association between Individual Food Groups, Limbic System White Matter Tracts, and Episodic Memory: Initial Data from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration (ALBION) Study.

(1) Background: Many studies link food intake with clinical cognitive outcomes, but evidence for brain biomarkers, such as memory-related limbic white matter (WM) tracts, is limited. We examined the association between food groups, limbic WM tracts integrity, and memory performance in community-dwelling individuals. (2) Methods: We included 117 non-demented individuals (ALBION study). Verbal and visual episodic memory tests were administered, and a composite z-score was calculated. Diffusion tensor imaging tractography was applied for limbic WM tracts (fornix-FX, cingulum bundle-CB, uncinate fasciculus-UF, hippocampal perforant pathway zone-hPPZ). Food intake was evaluated through four 24-h recalls. We applied linear regression models adjusted for demographics and energy intake. (3) Results: We found significant associations between (a) higher low-to-moderate alcohol intake and higher FX fractional anisotropy (FA), (b) higher full-fat dairy intake and lower hPPZ FA, and (c) higher red meat and cold cuts intake and lower hPPZ FA. None of the food groups was associated with memory performance. (4) Conclusions: Despite non-significant associations between food groups and memory, possibly due to participants' cognitive profile and/or compensatory mechanisms, the study documented a possible beneficial role of low-to-moderate alcohol and a harmful role of full-fat dairy and red meat and cold cuts on limbic WM tracts.

Betaine improves METH-induced depressive-like behavior and cognitive impairment by alleviating neuroinflammation via NLRP3 inflammasome inhibition

Methamphetamine abuse has been associated with central nervous system damage, contributing to the development of neuropsychiatric disorders such as depressive-like behavior and cognitive impairment. With the escalating prevalence of METH abuse, there is a pressing need to explore effective therapeutic interventions. Thus, the objective of this research was to investigate whether betaine can protect against depressive-like behavior and cognitive impairment induced by METH. Following intraperitoneal injections of METH in mice, varying doses of betaine were administered. Subsequently, the behavioral responses of mice and the impact of betaine intervention on METH-induced neural damage, synaptic plasticity, microglial activation, and NLRP3 inflammatory pathway activation were assessed. Administration 30 mg/kg and 100 mg/kg of betaine ameliorated METH-induced depressive-like behaviors in the open field test, tail suspension test, forced swimming test, and sucrose preference test and cognitive impairment in the novel object recognition test and Barnes maze test. Moreover, betaine exerted protective effects against METH-induced neural damage and reversed the reduced synaptic plasticity, including the decline in dendritic spine density, as well as alterations in the expression of hippocampal PSD95 and Synapsin-1. Additionally, betaine treatment suppressed hippocampal microglial activation induced by METH. Likewise, it also inhibited the activation of the hippocampal NLRP3 inflammasome pathway and reduced IL-1β and TNF-α release. These results collectively suggest that betaine's significant role in mitigating depressive-like behavior and cognitive impairment resulting from METH abuse, presenting potential applications in the prevention and treatment of substance addiction.

Acute Stress Effects on Statistical Learning and Episodic Memory.

Stress is widely considered to negatively impact hippocampal function, thus impairing episodic memory. However, the hippocampus is not merely the seat of episodic memory. Rather, it also (via distinct circuitry) supports statistical learning. On the basis of rodent work suggesting that stress may impair the hippocampal pathway involved in episodic memory while sparing or enhancing the pathway involved in statistical learning, we developed a behavioral experiment to investigate the effects of acute stress on both episodic memory and statistical learning in humans. Participants were randomly assigned to one of three conditions: stress (socially evaluated cold pressor) immediately before learning, stress ∼15 min before learning, or no stress. In the learning task, participants viewed a series of trial-unique scenes (allowing for episodic encoding of each image) in which certain scene categories reliably followed one another (allowing for statistical learning of associations between paired categories). Memory was assessed 24 hr later to isolate stress effects on encoding/learning rather than retrieval. We found modest support for our hypothesis that acute stress can amplify statistical learning: Only participants stressed ∼15 min in advance exhibited reliable evidence of learning across multiple measures. Furthermore, stress-induced cortisol levels predicted statistical learning retention 24 hr later. In contrast, episodic memory did not differ by stress condition, although we did find preliminary evidence that acute stress promoted memory for statistically predictable information and attenuated competition between statistical and episodic encoding. Together, these findings provide initial insights into how stress may differentially modulate learning processes within the hippocampus.

Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer’s disease

The etiopathogenesis of late-onset Alzheimer’s disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

Systemic Tumors Can Cause Molecular Changes in the Hippocampus That May Have an Impact on Behavior after Chronic Social Stress.

Evidence indicates that chronic social stress plays a significant role in the development of cancer and depression. Although their association is recognized, the precise physiological mechanism remains unknown. In our previous work, we observed that OF1 males subjected to chronic social defiance exhibited anhedonia, and those who developed tumors in the lung showed anxiety-associated behaviors. In this study, we observed that tumor-bearing OF1 mice presented higher levels of 3-HK, and this increase may be due to IDO. No differences in hippocampal catecholamine levels were observed. Our results suggest that a systemic tumor can induce molecular changes in the hippocampal kynurenine pathway that may impact behavior.

Shaping down syndrome brain cognitive and molecular changes due to aging using adult animals from the Ts66Yah murine model

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is associated with early neurodevelopmental changes and subsequently at adult age with the development of Alzheimer-like cognitive decline. However, the molecular mechanisms promoting brain pathology along aging are still missing. The novel Ts66Yah model represents an evolution of the Ts65Dn, used in characterizing the progression of brain degeneration, and it manifest phenotypes closer to human DS condition. In this study we performed a longitudinal analysis (3–9 months) of adult Ts66Yah mice. Our data support the behavioural alterations occurring in Ts66Yah mice at older age with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The evaluation of hippocampal molecular pathways in Ts66Yah mice, as effect of age, demonstrate the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-driven changes observed in those pathways occur early promoting altered brain development and the onset of a condition of premature aging. In turn, aging may account for the subsequent hippocampal deterioration that fall in characteristic neuropathological features. Besides, the analysis of sex influence in the alteration of hippocampal mechanisms demonstrate only a mild effect. Overall, data collected in Ts66Yah provide novel and consolidated insights, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.

Effect of Shenqi Jieyu formula on inflammatory response pathway in hippocampus of postpartum depression rats

AimTo investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the arachidonic acid metabolic pathway and nuclear factor kappa-B(NF-κB) signal path in the hippocampi of postpartum depression rats. MethodsThe rats were subcutaneous injected estradiol benzoate and progesterone to build PPD rat model. SJF, paroxetine hydrochloride and sEH inhibitor (AUDA) were used to treat PPD rats for 3 weeks. Then the morphological changes of hippocampi and various proteins were observed after that behavioral test were conducted in all 36 SD rats in six group: SJF, paroxetine, AUDA, PPD, sham and normal group. ResultsWeight, results of sucrose preference, upright times, total and center squares crossing decreased significantly (P < 0.01), whereas immobility time increased (P < 0.01). Results above were reversed in animals that in the SJF, paroxetine and AUDA groups. Hippocampal neurons in PPD rats partially degenerated with narrowed nuclei, increased autophagy and mitochondria bound to lysosomes were visible while the autophagy of hippocampal neurons in the paroxetine and AUDA group decreased, with a small amount of lysosomes. sEH, COX-2, 5-LOX, TNF-α, IL-1, IL-6, NF-κB p65, and Cor increased in hippocampi of PPD rats while EETs and 5-HT decreased. Protein expressions of Ibal, GFAP, p-IκBα, p65, and p-p65(S536)increased in PPD animals. Those changes were reversed by SJF, paroxetine and AUDA. Gene expressions of TNF-α, IL-1β, IL-6, 5-LOX, COX-2 and p65 increased in PPD rats and the changes of expression in these genes were reversed by paroxetine and AUDA. SJF reversed the gene expression changes of COX-2, TNF-α, and IL-1β. ConclusionSJF may have an analogous effect as sEH inhibitor to relieve depressive symptoms by suppressing inflammatory signaling pathways in hippocampi of PPD rats, which involves AA metabolic pathway and NF-κB signal pathway.

Recruitment of hippocampal and thalamic pathways to the central amygdala in the control of feeding behavior under novelty.

It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating can become maladaptive. Currently, the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance.

Effect of Cryptotanshinone on BDNF/TrkB Pathway in Hippocampus of Chronic Stress-induced Depression Rats

Background: Cryptotanshinone (CTS) is a monomer possessing a diverse array of pharmacological properties, primarily derived from Salvia miltiorrhiza. CTS was examined for its impact on rats with depression subjected to chronic unpredictable mild stress (CUMS) in this study. Materials and methods: Depression-like behavior of rats was established by isolated feeding combined with CUMS for 28 days, with CTS (7/14/21 mg/kg) or fluoxetine (5 mg/kg) administered once daily during this time. A comprehensive evaluation was performed, including body weight assessment, sucrose preference test, forced swimming test, and open field test. Hematoxylin-eosin staining was conducted to detect pathological changes in hippocampal CA1 neurons. Western blot analysis was employed to assess the brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), Ras-related C3 botulinum toxin substrate 1 (Rac1), and Cofilin expression levels in the hippocampus. Results: The depression rat model was successfully constructed. CTS can significantly improve impaired neurons in the hippocampal CA1 area, depression-like behaviors, and weight loss in CUMS-induced rats. Moreover, CTS reversed the down-regulation of BDNF/TrkB and Rac1/Cofilin in the CUMS-induced rats’ hippocampus. Conclusion: CTS demonstrates the therapeutic potential for depression by improving depression-like behaviors and ameliorating impaired neurons in the hippocampal CA1 area, and the mechanisms may involve the up-regulation of BDNF/TrkB and related signaling proteins Rac1/Cofilin.

Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson’s Disease Model by Modulating Hippo Signaling

Background:Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, following Alzheimer’s disease. The onset of PD is characterized by the loss of dopaminergic neurons in the substantia nigra. Stem cell therapy has great potential for the treatment of neurodegenerative diseases, and human nasal turbinate-derived stem cells (hNTSCs) have been found to share some characteristics with mesenchymal stem cells. Although the Hippo signaling pathway was originally thought to regulate cell size in organs, recent studies have shown that it can also control inflammation in neural cells.Methods:Dopaminergic neuron-like cells were differentiated from SH-SY5Y cells (DA-Like cells) and treated with 1-Methyl-4-phenylpyridinium iodide to stimulate Reactive oxidative species (ROS) production. A transwell assay was conducted to validate the effect of hNTSCs on the Hippo pathway. We generated an MPTP-induced PD mouse model and transplanted hNTSCs into the substantia nigra of PD mice via stereotaxic surgery. After five weeks of behavioral testing, the brain samples were validated by immunoblotting and immunostaining to confirm the niche control of hNTSCs.Results:In-vitro experiments showed that hNTSCs significantly increased cell survival and exerted anti-inflammatory effects by controlling ROS-mediated ER stress and hippocampal signaling pathway factors. Similarly, the in-vivo experiments demonstrated an increase in anti-inflammatory effects and cell survival rate. After transplantation of hNTSCs, the PD mouse model showed improved mobility and relief from PD symptoms.Conclusion:hNTSCs improved the survival rate of dopaminergic neurons by manipulating the hippocampal pathway through Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) by reducing inflammatory cytokines. In this study, we found that controlling the niche of hNTSCs had a therapeutic effect on PD lesions.

Acupressure bladder meridian alleviates anxiety disorder in rats by regulating MAPK and BDNF signal pathway

The aim of this study was to investigate the effects of acupressure bladder meridian (ABM) on anxiety in rats. Chronic stress was induced rats to establish rat anxiety model. Shuttle experiment and open field experiments of were used to measure behaviors. The levels of cytokines in serum and hippocampus of rats were detected. Brain neurotransmitters (dopamine, 5- hydroxy tryptamine, norepinephrine) were detected by Enzyme linked immunosorbent assay (ELISA) kits. Immunohistochemistry and western blotting were used to detect MAPK and BDNF signal pathway in hippocampus of rats. ABM significantly improve behaviors, decreased cytokine levels in serum and hippocampus. ABM restored the changes of neurotransmitters and significantly decreased protein expressions of MAPK signal pathway and increased protein expressions of BDNF signal pathway in hippocampus of rats. The results shown that ABM significantly improved anxiety via inhibition of MAPK signal pathway and increased BDNF signal pathway.