Telomere length and micronuclei trajectories in APP/PS1 mouse model of Alzheimer's disease: Correlating with cognitive impairment and brain amyloidosis in a sexually dimorphic manner.

Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age- and sex-related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild-type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6- to 14-month-old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age-related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aß40 and Aß42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female-biased manner.

Effects of ethanol extract from Bidens pilosa L. on spontaneous activity, learning and memory in aged rats.

BACKGROUND: Bidens pilosa L., a herbal medicine, is rich in flavonoids, but its anti-aging effect on neurocognitive functions is not well understood. In the present study, we investigated the effects of ethanol extract from Bidens pilosa L. (EEBP) on spontaneous activity, learning and memory in aged rats. METHODS: Forty aged (21.90 ±â€¯0.22 months) and 10 young (10 weeks) adult male Sprague-Dawley rats were divided into 5 groups, which were respectively treated orally with 0 mg/kg (young and aged control), 25 mg/kg, 50 mg/kg and 100 mg/kg of EEBP for 30 days consecutively. Then, the animals were examined with open-field, passive avoidance and Morris water maze tasks. RESULTS: In the open-field task, compared with the aged control, the EEBP animals exhibited more rearing (50 mg/kg, P < 0.01) and urination (50 mg/kg, P < 0.01), but less defecation (P < 0.05). In the passive avoidance task, the retention latencies were longer than those in the training phase in all other groups (P < 0.01) except the aged control (P > 0.05). Compared with the young control, the retention latency of the aged control decreased (P < 0.01), but that of the EEBP animals increased again (P < 0.05 vs. aged control). In the Morris water maze, the EEBP animals had shorter latency (100 mg/kg) and had more crossing times (25 mg/kg) in seeking the platform position (P < 0.05, vs. aged control). CONCLUSION: The results suggested that EEBP could affect the spontaneous activity and improve memory in aged animals and could have potential advantages for cognition improvement in aged populations.

Post-training reversible disconnection of the ventral hippocampal-basolateral amygdaloid circuits impairs consolidation of inhibitory avoidance memory in rats.

The ventral hippocampus (VH) and the basolateral amygdala (BLA) are both crucial in inhibitory avoidance (IA) memory. However, the exact role of the VH-BLA circuit in IA memory consolidation is unclear. This study investigated the effect of post-training reversible disconnection of the VH-BLA circuit in IA memory consolidation. Male Wistar rats with implanted guide cannulae were trained with a one-trial IA task, then received immediate intracerebral injections of muscimol or saline, and were tested 24 h later. Muscimol injection into the bilateral BLA, or the unilateral VH and contralateral BLA, but not the unilateral VH and ipsilateral BLA, significantly decreased the retention latencies (versus saline treatment). The results suggest that the VH-BLA circuit could be an important circuit to modulate consolidation of IA memory in rats.

Effects of treadmill exercise intensity on spatial working memory and long-term memory in rats.

AIMS: Moderate exercise promotes learning and memory. Most studies mainly focused on memory exercise effects of in the ageing and patients. There is lack of quantitative research about effect of regular exercise intensity on different memory types in normal subjects. Present study investigated the effects of different intensities of treadmill exercise on working memory and long-term memory. MAIN METHODS: Fifty female Wistar rats were trained by T-maze delayed spatial alternation (DSA) task with 3 delays (10s, 60s and 300s). Then they got a 30min treadmill exercise for 30days in 4 intensities (control, 0m/min; lower, 15m/min; middle, 20m/min, and higher, 30m/min). Then animals were tested in DSA, passive avoidance and Morris water maze tasks. KEY FINDINGS: 1. Exercise increased the neuronal density of hippocampal subregions (CA1, CA3 and dentate gyrus) vs. naïve/control. 2. In DSA task, all groups have similar baseline, lower intensity improved 10s delay accuracy vs. baseline/control; middle and higher intensities improved 300s delay accuracy vs. baseline/control. 3. In water maze learning, all groups successfully found the platform, but middle intensity improved platform field crossing times vs. control in test phase. SIGNIFICANCE: Present results suggested that treadmill exercise can improve long-term spatial memory and working memory; lower intensity benefits to short-term delayed working memory, and middle or higher intensity benefits to long-term delayed working memory. There was an inverted U dose-effect relationship between exercise intensity and memory performance, but exercise -working memory effect was impacted by delay duration.

[Effect of prefrontal infralimbic cortex GABAA receptor agitating on passive avoidance memory consolidation of rats].

In this study, one-trial step-through task was applied to reveal the effect of prefrontal infralimbic cortex GABAA receptor agitating on passive avoidance memory consolidation in rats. Immediately after training (with shock), GABAA receptor agonist, muscimol (0.5 µg/0.25 µL) or saline (0.25 µL) was infused into the test animal's infralimbic cortex, then, the latencies of rats stepping through the dark room were recorded. Meanwhile, local EEG power was adopted as index of the inactivation effect of muscimol. The step-through latencies of muscimol group were comparable(P>0.05)with saline group, but their local EEG power had decreased significantly (P<0.05). These results suggest that the inactivation of infralimbic cortex would not demolish the passive avoidance memory consolidation of rats.

[Impairment effects of tail suspension stress on spatial memory and its reversal learning in mice].

Present work investigated the effects of tail suspension stress (TSS) on spatial memory acquisition, consolidation, and its reversal learning in mice. Eighty-one adult male KM mice were divided into four groups (each group including a TSS subgroup and its control subgroup): absolute spatial memory acquisition and consolidation groups (group AA and CA); relative spatial memory acquisition and consolidation groups (group AR and CR). TSS (20 min) was performed immediately before (acquisition) or after (consolidation) a daily training. Results showed that there was no significant difference between control animals and TSS animals in each group in early spatial memory training days (5-8 d of training). Along with training, the performance of control animals improved significantly, but the performance of TSS animals improved slightly (group AA, CA and AR) or even did not change (group CR) (P<0.01). Reversal learning was also impaired in TSS animals (P<0.01). The results indicated that TSS could impair spatial memory acquisition, consolidation and reversal learning (especially the relative spatial memory consolidation and its reversal learning) in mice.

[Hippocampal-prefrontal cortical circuit and working memory].

The study on learning and memory is one of the striking subjects in neuroscience today. In the cerebral cortex, it is has been proved that, the hippocampus, the prefrontal cortex and the hippocampal-prefrontal cortical circuit are important to working memory. In this paper, we review findings of the anatomical and electrophysiological characteristics of the hippocampal-prefrontal cortical circuit and the roles of these three structures in working memory.

The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats.

Although prefrontal and hippocampal neurons are critical for spatial working memory, the function of glial cells in spatial working memory remains uncertain. In this study we investigated the function of glial cells in rats' working memory. The glial cells of rat brain were inhibited by intracerebroventricular (icv) injection of fluorocitrate (FC). The effects of FC on the glial cells were examined by using electroencephalogram (EEG) recordings and delayed spatial alternation tasks. After icv injection of 10 microL of 0.5 nmol/L or 5 nmol/L FC, the EEG power spectrum recorded from the hippocampus increased, but the power spectrum for the prefrontal cortex did not change, and working memory was unaffected. Following an icv injection of 10 microL of 20 nmol/L FC, the EEG power spectra in both the prefrontal cortex and the hippocampus increased, and working memory improved. The icv injection of 10 microL of 50 nmol/L FC, the EEG power spectra in both the prefrontal cortex and in the hippocampus decreased, and working memory was impaired. These results suggest that spatial working memory is affected by centrally administered FC, but only if there are changes in the EEG power spectrum in the prefrontal cortex. Presumably, the prefrontal glial cells relate to the working memory.

Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats.

Wistar rats, treated with the GABA(A) receptor agonist muscimol, were used to investigate the role of the hippocampal-prelimbic cortical (Hip-PLC) circuit in spatial learning in the Morris water maze task, and in passive avoidance learning in the step-through task. In the water maze task, animals were trained for three consecutive days and tested 24 h after the end of training. In the step-through task, the animals were trained once and tested 24h after training. On the training days, daily infusion of muscimol (0.5 microg/0.25 microl) was given (1) bilaterally to the ventral hippocampus (vHip), (2) bilaterally to the prelimbic cortex (PLC), (3) to the unilateral vHip and the ipsilateral PLC, or (4) for disconnecting the Hip-PLC circuit, to both the unilateral vHip and the contralateral PLC 30 min before training. The results showed that inhibition of the vHip resulted in disruption of performance in both tasks. Inhibition of the PLC produced impaired water maze performance, but had no effect on the step-through task. Disconnection of the Hip-PLC circuit produced similar effects to PLC inhibition. However, simultaneous inhibition of the unilateral vHip and the ipsilateral PLC had little effect on performance of the water maze task. The results suggested that spatial learning depends on the Hip-PLC circuit, whereas passive avoidance learning is independent of this circuit.

Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats.

There is a unidirectional, ipsilateral and monosynaptic projection from the hippocampus to the prefrontal cortex. The cognitive function of hippocampal-prefrontal cortical circuit is not well established. In this paper, we use muscimol treated rats to investigate the roles of the hippocampal-prefrontal cortical circuits in spatial working memory, as assessed with a delayed spatial alternation task. First of all, the effect of muscimol on EEG power of infusion area was observed for confirmation of the dosage of muscimol to inhibit the function of infusion area. The results show that the EEG power of the ventral hippocampus and the prelimbic area of the prefrontal cortex were inhibited by local infusion of muscimol (0.5 microg in 0.25 microl PBS) into the above areas, respectively. Delayed alternation performance was significantly impaired when muscimol at this dosage was infused (1) bilaterally into the ventral hippocampus, (2) bilaterally into the prelimbic area, (3) unilaterally into the ventral hippocampus and simultaneously contralaterally into the prelimbic area. Infusion of muscimol either unilaterally into the ventral hippocampus or unilaterally into the prelimbic area did not impair delayed alternation performance. The present results suggest that any structures in this circuit is damaged or inhibited bilaterally, the spatial working memory will be disrupted. It means the hippocampal-prefrontal cortical circuit plays an important role in spatial working memory.