Neuroscience Letters最新文献

Preclinical data have repeatedly shown learning and memory disruption following administration of the bacterial endotoxin lipopolysaccharide (LPS). Normal aging is reported to enhance vulnerability to LPS-induced cognitive impairments. However, a limitation is the primary use of male subjects. Recent evidence indicates sex-related differences in vulnerability to LPS-induced cognitive deficits [1,2], with young females showing resilience. Whether middle-aged females are susceptible to LPS-induced cognitive impairment is unknown. The current experiment compared associative learning in young and middle-aged male and female C57BL/6J mice following a systemic LPS challenge. While LPS impaired acquisition of the two-way active avoidance conditioning task in adult and middle-aged males, females' learning was unaffected. The sex difference in LPS-induced cognitive impairments appears unrelated to responsivity to LPS, as males and females mount a comparable sickness-like response. Additionally, relative to males, females produce higher brain levels of interleukin-6 (IL-6) and comparable splenic IL-6 levels following LPS. These data demonstrate that female resilience to LPS-induced learning deficits persists into middle age, whereas males are vulnerable as both young and middle-aged adults. Our findings confirm the importance of considering sex as a biological variable and extend the existing literature by evaluating sex-related responsivity to LPS in middle-aged males and females.

Objectives: Taraxasterol is the active ingredient of Taraxacum officinale which has been used in traditional medicine for its several therapeutic effects. This study aims first to evaluate the potential spinal/supraspinal and peripheral/visceral antinociceptive effect of taraxasterol and then to investigate the contribution of GABAergic, opioidergic systems, and K_ATP channels to its antinociceptive effect.

Methods: The antinociceptive activity of taraxasterol (2.5, 5, and 10 mg/kg i.p.) was investigated with hot-plate, tail-immersion, and acetic acid-induced abdominal writhing tests (for supraspinal, spinal, peripheral/visceral pain evaluation, respectively) in BALB/c male mice, and percentage of possible maximum effect (MPE%) values were calculated. Mechanism of action studies were performed by pre-administering bicuculline, naloxone, and glibenclamide.

Results: Taraxasterol increased the MPE% values in hot-plate and tail-immersion tests at 2.5, 5, and 10 mg/kg doses (P < 0.001) and decreased the mean number of writhes at 10 mg/kg in the abdominal writhing test (P < 0.05). Naloxone and bicuculline pre-administration reversed the antinociceptive effect of taraxasterol in hot-plate and tail-immersion tests and it had no effect in the abdominal writhing test. Pre-administration of glibenclamide reversed the antinociceptive effect of taraxasterol in all tests.

Conclusion: Our study is the first to show the involvement of GABAergic and opioidergic systems in the antinociceptive effect of taraxasterol in supraspinal and spinal pain tests, and K_ATP channels in tests evaluating supraspinal, spinal, and peripheral pain pathways. Taraxasterol is a potential new herbal medicine that can be used for pain control.

Panic disorder is more frequent in women than in men. In women, vulnerability to panic is enhanced during the late luteal phase of the menstrual cycle. At this time secretion of progesterone and its neuroactive metabolite allopregnanolone (ALLO), which acts as a positive allosteric modulator of the actions of GABA at GABA_A receptors, decline sharply. In female rats, responsiveness to a hypoxic panicogenic challenge increases during the late diestrus (LD) phase as ALLO concentration in the brain falls. During LD, short-term treatment with fluoxetine at a low dose (1.75 mg/kg i.p.) blocked panic-related escape behavior in response to hypoxia. At this dose fluoxetine increases brain concentration of ALLO without affecting 5-HT levels, thereby stabilizing brain ALLO concentration. We here report that the panicolytic-like effect of fluoxetine during LD is prevented by microinjection of the GABA_A receptor antagonist bicuculline (5 pmol) into the dorsal periaqueductal gray (dPAG), a key panic-related area. This result suggests that fluoxetine's effect is indirectly mediated via a GABAergic mechanism in the dPAG and highlights the important role of changes in GABAergic tone in regulating neuronal excitability in the panic circuitry during the estrous cycle. It also points to the potential for using short-term, low dose fluoxetine as an anti-panic medication in women.

Post-traumatic stress disorder (PTSD), is a severe anxiety disorder characterized by associative fear conditioning. Single prolonged stress (SPS) is a widely accepted reliable animal model to stimulate PTSD. Agmatine is an endogenous neuromodulator of stress; however, its effect on PTSD remains to be investigated. This study explored the role of agmatine in conditioned fear response (CFR) in PTSD and highlighted the role of imidazoline receptors in the effect of agmatine. Intra-cerebroventricular (icv) surgery was done in order to facilitate drug administration. Animals were subjected to SPS. Agmatine and the involvement of imidazoline receptors (I₁ and I₂) were assessed for their effect in fear conditioning apparatus. During weeks 1, 2, and 3, in CFR, agmatine (40 µg/rat, icv) showed significantly decreased freezing time whereas other doses of agmatine (10 and 20 µg/rat, icv). Imidazoline (I₁ and I₂) receptor agonists Moxonidine (25 µg/rat, icv) and 2-BFI, (10 µg/rat, icv) respectively, at their sub-effective doses, with a submaximal dose of agmatine (20 µg/rat, icv) significantly decreased the altered freezing time during weeks 1, 2 and 3 compared to SPS animals. Moreover, the effective dose of agmatine (40 µg/rat, icv) with imidazoline (I₁ and I₂) receptor antagonists Efaroxan (10 µg/rat, icv) and Idazoxan (4 µg/rat, icv) respectively does not reversed the effect of agmatine on freezing. Agmatine and its combination with I₁ and I₂ agonists, normalized the altered freezing behavior, corticosterone level, organ coefficient of adrenal gland, neuroinflammatory and neurotrophic factor due to SPS during CFR projecting its strong therapeutic effect in SPS induced PTSD.

Estrogen has demonstrated beneficial effects; however, it can also have unfavorable effects. Phytoestrogens are present in many consumable products and commonly used as supplements. These are of interest as they may have beneficial effects on mood with fewer undesirable effects on reproductive tissues. This study investigated the anxiolytic-like effects of the phytoestrogens genistein and daidzein on ovariectomized (Ovx) rats and their effects on the expression of uterine estrogen receptors (ER) and brain monoamines. In experiment 1, Ovx rats received either vehicle, 17β-estradiol, or 0.25 - 1 mg/kg of genistein or daidzein for 4 weeks before behavioral tests of anxiety. In experiment 2, we assessed the therapeutic effects of genistein and daidzein. The ovariectomies were used to induce anxiety, so the treatments were started 3 weeks post-ovariectomy. The Ovx rats received vehicle, 17β-estradiol, or 0.25 mg/kg of genistein or daidzein daily for 4 weeks before behavioral tests. We found daidzein and genistein comparable to 17β-estradiol in their anxiolytic-like effects. Further, while 17β-estradiol decreased body weight gain, increased uterine weight, and increased the uterine ERα/ERβ ratio, neither genistein nor daidzein had these undesirable effects. The alterations in brain monoamines following genistein or daidzein treatments were somewhat different from those seen after 17β-estradiol treatment. In conclusion, daily daidzein or genistein administration for 4 weeks did not negatively affect body weight, food intake, uterine tissue, uterine ER expressions, or ERα/ERβ ratio but demonstrated anxiolytic-like effects on Ovx rats. We conclude that low-dose (0.25 mg/kg) genistein or daidzein can alleviate anxiety in a female anxious rat model.

Combined and highly active anti-retroviral therapies (cART) have transitioned HIV into a more chronic disease. Roughly half of people living with HIV (PLWH) still experience neurocognitive disorders, albeit less severely than in the pre-cART era. Sex-related effects on memory/cognition remain understudied, although the percentage of PLWH that are female has increased. We utilized a transgenic mouse model of HIV that conditionally expresses HIV-1 Tat_1-86 in the CNS to examine cognitive behaviors and the expression of biomarkers related to learning and memory in both sexes. Tat+ males exhibited deficits in spatial learning/memory and object recognition, while Tat+ females showed enhanced fear memory. We investigated the involvement of activity-regulated cytoskeleton-associated protein (Arc), which is induced by novel experience related to learning/memory. We observed hippocampal Arc induction following foot shock in Tat+ females but not Tat+ males. Hippocampal levels of Arc, amyloid β (Aβ) monomers/oligomers and pCREB were altered in a sex-specific manner. CREB activity, which is highly associated with Arc induction, was reduced only in Tat+ males. Tat exposure also decreased Arc expression in cultured human neurons. Thus, HIV-1 Tat effects on CREB/Arc signaling may differ between sexes, contributing to differences in cognitive deficits observed here and in PLWH.

Objective: Long non-coding RNA (lncRNA) has been playing an increasingly significant role in neuropathic pain (NP). This study aimed to investigate the clinical significance and mechanism of LncRNA ZNFX1 antisense RNA 1 (ZFAS1) in NP.

Methods: 92 patients with NP and healthy controls were enrolled, and a rat NP model was constructed by chronic constrictive injury (CCI). LPS-induced microglia BV2 cells were used to construct an in vitro cellular model. RT-qPCR analysis of the mRNA levels of ZFAS1, miR-421, and Iba-1 (markers of microglia activation). Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were used to assess mechanosensitive and thermal nociceptive allergic responses. ELISA assay for pro-inflammatory factors and anti-inflammatory factors expression. ROC assay for the diagnostic value of ZFAS1. Validation of the targeting between ZFAS1 and miR-421 by dual luciferase reporter assay.

Results: ZFAS1 significantly increased while miR-421 significantly decreased in individuals with NP, in a rat model of CCI, and in LPS-induced microglial cells. Functionally, miR-421 directly targeted ZFAS1. ZFAS1 levels could significantly differentiate between NP patients and control (AUC = 0.910). Low expression of ZFAS1 significantly alleviated PWL and PWT in CCI rats. Elevated neuro-proinflammatory factors and decreased anti-inflammatory factors in CCI rats were significantly reversed by low expression of ZFAS1, but this is partially weakened by low expression of miR-421. Moreover, silencing ZFAS1 hindered the upregulation of Iba-1 expression induced by LPS, which was rescued significantly by miR-421.

Conclusion: Elevated ZFAS1 is a potential bio-diagnostic marker for NP. Inhibition of ZFAS1 may alleviate NP progression by inhibiting microglia activation and neuro-inflammatory responses.

Pain and psychological stress are intricately linked, with sex differences evident in disorders associated with both systems. Glutamatergic signalling in the central nervous system is influenced by gonadal hormones via the hypothalamic-pituitary-adrenal axis and is central in pain research. Emerging evidence supports an important role for the gut microbiota in influencing pain signalling. Here, the functional activity of excitatory amino acid transporters (EAATs) in the anterior cingulate cortex (ACC) and lumbosacral spinal cord of male and female Wistar-Kyoto rats, an animal model of comorbid visceral hypersensitivity and enhanced stress responsivity, was investigated across the oestrous cycle. Correlations between the gut microbiota and changes in the functional activity of the central glutamatergic system were also investigated. EAAT function in the lumbosacral spinal cord was similar between males and females across the oestrous cycle. EAAT function was higher in the ACC of dioestrus females compared to proestrus and oestrus females. In males, aspartate uptake in the ACC positively correlated with Bacteroides, while aspartate uptake in the spinal cord positively correlated with the relative abundance of Lachnospiraceae NK4A136. Positive associations with aspartate uptake in the spinal cord were also observed for Alistipes and Bifidobacterium during oestrus, and Eubacterium coprostanoligenes during proestrus. Clostridium sensu stricto1 was negatively associated with aspartate uptake in the ACC in males and dioestrus females. These data indicate that glutamate metabolism in the ACC is oestrous stage-dependent and that short-chain fatty acid-producing bacteria are positively correlated with aspartate uptake in males and during specific oestrous stages in females.

Postoperative cognitive dysfunction (POCD) is a common cognitive challenge faced by older adults. One of the key contributors to the development of POCD is neuroinflammation induced by microglia. Resveratrol has emerged as a promising candidate for the prevention of cognitive decline. Previous studies have demonstrated its potential in alleviating cognitive deterioration, yielding encouraging results. Nonetheless, the mechanism of resveratrol improving cognitive function remains unclear. Therefore, we assessed the effect of resveratrol in both aged POCD model mice and BV2 cells on CX3CL1/CX3CR1 axis, a critical signaling pathway mediating microglial activity. Both in vitro and in vivo experiments have revealed that pre-administration of resveratrol not only mitigates cognitive deficits but also significantly reduces the levels of inflammatory cytokines. Additionally, it enhanced the expression of SIRT1 and CX3CR1 within the hippocampal region. We also evaluated the impact of resveratrol on CX3CR1 siRNA transfected BV2 cells. Delete of CX3CR1 reversed the preventive role of resveratrol. Our findings implied that resveratrol might inhibit microglial activation and improve cognition by mediating CX3CL1/CX3CR1 signaling.

This study established an animal model of comorbid depression and insomnia by combining chronic unpredictable mild stress (CUMS) with sleep deprivation (SD). The pathogenesis of comorbid depression and insomnia may be associated with impaired AMPK/FOXO3a signaling, which mediates autophagy inhibition, leading to decreased pineal melatonin secretion. The findings revealed that CUMS + SD rats exhibited more pronounced depression-like behaviors, sleep disorders, increased central oxidative stress, and exacerbated neuroinflammation, accompanied by reduced levels of 5-hydroxytryptophan (5-HT) and melatonin in the pineal gland. Notably, further investigations revealed that impaired mitochondrial autophagy in the pineal gland is closely linked to the significant suppression of AMPK/FOXO3a signaling. The combined intervention of venlafaxine and melatonin effectively ameliorated the impaired mitochondrial autophagy in the pineal gland of CUMS + SD rats and stimulated melatonin secretion. Consequently, the study proposes that dysfunctional mitochondrial autophagy regulated by the AMPK/FOXO3a pathway can influence melatonin secretion, thereby playing a pivotal role in the pathogenesis of depression combined with insomnia.