Increase In Hippocampal Levels Research Articles

Beneficial effects of Lactococcus lactis subsp. cremoris LL95 treatment in an LPS-induced depression-like model in mice

Clinical evidence suggests that neuroinflammation, activation of the immune system, and the composition of the intestinal microbiota are involved in the pathology of depression. This study evaluated the effectiveness of a probiotic intervention using Lactococcus lactis subsp. cremoris LL95 in ameliorating mood disorders in a lipopolysaccharide (LPS)-induced depression-like mouse model. C57BL/6 mice were randomly divided into four groups and treated with 5 mg/kg LPS via intraperitoneal injection to induce depression-like symptoms, followed by oral administration of LL95 for one week (1 × 109 CFU/mouse). The animals were then subjected to a series of behavioral assessments, including open field, sucrose preference, and forced swimming tests. In addition, we evaluated the levels of reactive oxygen species, tumor necrosis factor-α, and interleukin-1β in the hippocampal tissues of these animals, and also determined their fecal lactic acid bacteria (LAB) content. LL95 intervention improved LPS-induced depression-like behaviors in mice, including decreased sucrose preference and increased immobility time in the forced swim test. LL95 treatment reversed the LPS-induced increase in hippocampal levels of reactive oxygen species and tumor necrosis factor-α, and of interleukin-1β to a lesser extent. Furthermore, LL95 intervention increased the fecal LAB content in these animals, suggesting changes in the gut microbiota. These findings suggest that LL95 exerts antidepressant-like effects in LPS-induced depression, which may be attributed to modulation of the oxidative status and pro-inflammatory cytokine expression in the hippocampus and alteration in the LAB content of the gut microbiota.

Does (\u2009\u2212)-epigallocatechin-3-gallate protect the neurotoxicity induced by bisphenol A in vivo?

Bisphenol A (BPA) is one of the chemicals that is firmly accompanied by hippocampal neuronal injury. As oxidative stress appears to be a major contributor to neurotoxicity induced by BPA, antioxidants with remarkable neuroprotective effects can play a valuable protective role. Around the world, ( −)-epigallocatechin-3-gallate (EGCG) was one of the most popular antioxidants that could exert a beneficial neuroprotective role. Here, we examined the potential efficiency of EGCG against neurotoxicity induced by BPA in the hippocampal CA3 region of the rat model. This study revealed that EGCG was unable to abrogate the significant decrease in circulating adiponectin level and hippocampal superoxide dismutase activity as well as an increase in hippocampal levels of nitric oxide and malondialdehyde. Notably, EGCG failed to antagonize the oxidative inhibitory effect of BPA on hippocampal neurotransmission and its associated cognitive deficits. In addition, the histopathological examination with immunohistochemical detection of caspase-3 and NF-kB/p65 emphasized that EGCG failed to protect hippocampal CA3 neurons from apoptotic and necrotic effects induced by BPA. Our study revealed that EGCG showed no protective role against the neurotoxic effect caused by BPA, which may be attributed to its failure to counteract the BPA-induced oxidative stress in vivo. The controversial effect is probably related to EGCG’s ability to impede BPA glucuronidation and thus, its detoxification. That inference requires further additional experimental and clinical studies.Graphical abstract

Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) α and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ERα, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (ovariectomized controls). Rats initially receiving estradiol received either another estradiol (continuous estradiol) or a vehicle (previous estradiol) capsule. One month later, hippocampi were dissected and processed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ERα and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ERα as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause.

Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network.

d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.

What is the combined effect of intense intermittent exercise and Ginkgo biloba plant on the brain neurotrophic factors levels, and learning and memory in young rats?

The present study was conducted to investigate the effect of intense intermittent exercise and Ginkgo biloba on the hippocampal levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) and also memory and learning in young rats. Forty two eight-week-old rats were randomly divided into six groups including control, low dose of Ginkgo biloba (65 mg/kg), high dose of Ginkgo biloba (100 mg/kg), exercise, exercise + low dose of Ginkgo biloba, exercise + high dose of Ginkgo biloba. The exercise protocol or Ginkgo biloba administration was six days a week for six weeks. The hippocampal levels of BDNF and NT-4 were measured by ELISA method, and learning and memory were evaluated by Morris water maze test in all groups. Data were analyzed using SPSS software. Increase in hippocampal levels of BDNF and NT-4 appeared following exercise (p < 0.01). The levels do not change following exercise + Ginkgo biloba administration. However, the NT-4 level decreased in the high dose of Ginkgo biloba group (p < 0.01). Disorder in learning and memory was indicated following the use of low dose of Ginkgo biloba or exercise + low dose Ginkgo biloba administration (p < 0.001). Learning elevated in the exercise group (p < 0.05). Exercise in young rats may increase brain neurotrophin levels and lead to improved learning. The preventative or protective role of Ginkgo biloba against some diseases has been suggested, but its consumption in young athletes is recommended with caution.

Antidepressant-like effect of pramipexole in an inflammatory model of depression

Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson’s disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1β levels and reversed LPS-induced increase in its content in mice hippocampus⋅ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.

Prior stressor exposure delays the recovery of surgery-induced cognitive impairment and prolongs neuroinflammation in aged rats

Increasing evidence indicates that stress potentiates pro-inflammatory response to a subsequent peripheral immune challenge. The present study investigated if prior exposure to inescapable tailshock (IS) delayed the recovery of surgery-induced spatial learning and memory impairment and prolonged hippocampus interleukin (IL)-1β and IL-6 expression. MethodsA total of 192 aged rats were trained with Morris water-maze (MWM) for 6 consecutive days. A single session of inescapable tailshock was performed on day 6 after training. Then, the rats subjected to partial hepatectomy. Hippocampal-dependent spatial learning and memory were assessed on postoperative days 1, 3 and 7. The cytokines IL-1β and IL-6 and ionized calcium binding adaptor protein (Iba)-1 were measured at each time point. Cluster of differentiation 200 (CD200) was also measured to explore potential mechanisms of glial cell activation. ResultsExposure of IS alone failed to affect the latency to platform and increase hippocampal cytokine levels at each time point. However, IS alone significantly increased the expression levels of Iba-1. A prolonged latency and additional significant increase in hippocampal levels of IL-1β and IL-6 were observed when partial hepatectomy was performed in aged rats exposed to IS 24h later. The combination of IS and surgical trauma dramatically upregulated the levels of Iba-1 and significantly decreased the expression of CD200. ConclusionIS alone failed to induce cognitive deficits and increase pro-inflammatory cytokines expression. However, IS delayed the recovery of surgery-induced spatial learning and memory impairment and prolonged pro-inflammatory response to the subsequent surgery challenge.

Preventive effects of multisensory rehabilitation on development of cognitive dysfunction following systemic inflammation in aged rats

Systemic inflammation can trigger transient or longer-lasting cognitive impairments, particularly in elderly patients. However, its pathogenesis has not been sufficiently clarified. In this study, we explored the potential effects of multisensory rehabilitation on cognitive dysfunction following systemic inflammation using an animal model. Aged male Wister rats were randomly injected intraperitoneally with either saline (control) or lipopolysaccharide (LPS; 5mg/kg). After injection, both groups of rats were randomly assigned to either of two housing conditions (n=8 in each condition): a standard cage environment (SC group) or a multisensory early rehabilitation environment (ER group). Cognitive function was examined after 7days in the assigned environmental condition using a novel object recognition test. In the SC group, the LPS-treated rats showed impaired cognitive function compared with the control animals. These memory deficits were positively correlated with the levels of both tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus. On the other hand, in the LPS-treated ER group, neither cognitive impairment nor an increase in hippocampal levels of both TNF-α and IL-1β was found. These results imply that early rehabilitation (ER) intervention may be effective in preventing cognitive dysfunction following systemic inflammation via its anti-neuroinflammatory effects.

Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer's transgenic mice

The efficacy of antihypertensive agents in Alzheimer's disease (AD) is controversial. It has been tested here whether some antihypertensive drugs might influence AD through mechanisms independent of blood pressure-lowering activity. The effects of treatment with the antihypertensive propranolol on cognition and AD-related markers have been studied in the Tg2576 mouse model of AD. Propranolol, at a lower dose than that used as antihypertensive (5 mg/kg, 6 wk), attenuated cognitive impairments shown by Tg2576 mice aged 9 months in the novel object recognition and fear conditioning tests. Propranolol was also able to counteract the increases in hippocampal levels of Aβ(42) present in Tg2576 mice. This effect was accompanied by an increased expression of insulin degrading enzyme. Changes in markers of synaptic pathology, as shown by decreases in phosphorylation of Akt and in the expression of BDNF in Tg2676 mice, were also counteracted by propranolol treatment. Tau hyperphosphorylation shown by Tg2576 mice was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to an increase of GSK3β phosphorylation (inactive form) and a decreased JNK1 expression. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for AD.

5-HT4 Receptor Stimulation Leads to Soluble AβPPα Production Through MMP-9 Upregulation

Serotonin 4 (5-HT4) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer's disease (AD) through regulation of the production of soluble amyloid-β protein precursor alpha (sAβPPα). To analyze the relationship between 5-HT4 receptor signaling and sAβPPα production, we stably transfected H4 cells with AβPP and 5-HT4 receptor (H4/AβPP/5-HT4 cells). We found that 24-h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sAβPPα levels, whereas knockdown with MMP-9 siRNA decreased sAβPPα levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-β peptide (Aβ) deposition, there was an increase in hippocampal levels of sAβPPα, C-terminal fragment α, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, Aβ40. Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves AβPP through α-secretase-like activity, leading to an increase of sAβPPα levels and a reduction of Aβ load.

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute (30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements.

Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder

Previous studies have demonstrated that rats subjected to single prolonged stress (SPS) exhibit posttraumatic stress disorder (PTSD)-like symptoms, such as enhanced contextual fear in response to trauma-related and trauma-unrelated events. Furthermore, we previously reported that upregulation of hippocampal glycine transporter 1 (GlyT-1) mRNA after context exposure could be the initial mechanism underlying impaired fear extinction in SPS rats. To clarify the involvement of the hippocampal glycinergic system in impaired fear extinction in SPS rats, we measured the time course of changes in the duration of freezing and the hippocampal levels of Gly-T1 mRNA using contextual fear conditioning (FC) and extinction training. We also used in vivo microdialysis to measure the concentration of extracellular glycine in the hippocampus during the time interval between FC and the first context exposure. SPS rats exhibited increased and sustained contextual fear responses. The enhanced contextual fear response in SPS rats was associated with a sustained increase in hippocampal levels of Gly-T1 mRNA after FC relative to sham rats, and by a decrease in the extracellular glycine concentration. GlyT-1 mRNA levels in rats that underwent repeated extinction training were significantly lower than in rats that did not undergo extinction training. These findings indicate that reduced activity of the hippocampal glycinergic system could be closely involved in impaired fear extinction in SPS rats, suggesting that activation of the glycinergic system by d-cycloserine or GlyT-1 inhibitors may ameliorate the impairment of fear extinction.

Glial Activation Links Early‐Life Seizures and Long‐Term Neurologic Dysfunction: Evidence Using a Small Molecule Inhibitor of Proinflammatory Cytokine Upregulation

Early-life seizures increase vulnerability to subsequent neurologic insult. We tested the hypothesis that early-life seizures increase susceptibility to later neurologic injury by causing chronic glial activation. To determine the mechanisms by which glial activation may modulate neurologic injury, we examined both acute changes in proinflammatory cytokines and long-term changes in astrocyte and microglial activation and astrocyte glutamate transporters in a "two-hit" model of kainic acid (KA)-induced seizures. Postnatal day (P) 15 male rats were administered KA or phosphate buffered saline (PBS). On P45 animals either received a second treatment of KA or PBS. On P55, control (PBS-PBS), early-life seizure (KA-PBS), adult seizure (PBS-KA), and "two-hit" (KA-KA) groups were examined for astrocyte and microglial activation, alteration in glutamate transporters, and expression of the glial protein, clusterin. P15 seizures resulted in an acute increase in hippocampal levels of IL-1beta and S100B, followed by behavioral impairment and long-term increases in GFAP and S100B. Animals in the "two-hit" group showed greater microglial activation, neurologic injury, and susceptibility to seizures compared to the adult seizure group. Glutamate transporters increased following seizures but did not differ between these two groups. Treatment with Minozac, a small molecule inhibitor of proinflammatory cytokine upregulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment. These data suggest that glial activation following early-life seizures results in increased susceptibility to seizures in adulthood, in part through priming microglia and enhanced microglial activation. Glial activation may be a novel therapeutic target in pediatric epilepsy.

Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat.

Brain aging as well as brain degenerative processes with accompanying cognitive impairments are generally associated with hyperactivity of the hypothalamus-pituitary-adrenal axis, the end product of which, the glucocorticoid hormone, has been warranted the role of cell damage primum movens ("cascade hypothesis"). However, chronic inflammatory activity occurs in the hippocampus of aged rats as well as in the brain of Alzheimer's disease patients. The concomitant increase in the secretion of the glucocorticoid hormone, the endogenous anti-inflammatory and pro-inflammatory markers, has prompted us to investigate the two phenomena in the aging rat, and to work out its meaning. This study shows that: (I) interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and prostaglandin E(2) (PGE(2)) increase with age in the rats hippocampus, and (II) chronic oral treatment with celecoxib, a selective cycloxygenase-2 (COX-2) inhibitor, is able to contrast the age-dependent increase in hippocampal levels of pro-inflammatory markers and circulating anti-inflammatory corticosterone, provided that it is started at an early stage of aging. Under these conditions, age-related impairments in cognitive ability may be ameliorated. Taken together, these results indicate that there is a natural tendency to offset the age-dependent increase in brain inflammatory processes via the homeostatic increase of the circulating glucocorticoid hormone.

CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor.

CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.