Introduction: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain’s inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. Methods: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1β (IL-1β) levels were significantly higher in the LPS1+SD group than in the Saline group. Conclusion: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone.

Physiologically, sleep is a complex, necessary, and homeostatic process [1]. Studies in animals and humans have shown that the homeostatic response to increased information consolidation occurs during sleep [2]. Although sleep is a fundamental component of a healthy lifestyle, millions worldwide suffer from the epidemic of sleep deprivation (SD) [3]. Chronic SD is a growing problem in many modern countries [4]. Animal studies have also shown the negative effects of SD on cognitive functions through behavioral tests such as the Morris water maze (MWM) [5, 6], the passive avoidance, the novel objective recognition [7], and long-term potentiation (LTP) [8, 9]. The LTP model is one of the main experimental models for studying the synaptic basis of learning and memory in vertebrates [10]. Protein synthesis and synaptic plasticity may be affected by SD, although the exact molecular mechanisms involved are not yet fully understood. In this respect, inflammation may play a role in synaptic plasticity and protein synthesis [11]. Insomnia impairs learning and memory. In addition, it alters the concentration of inflammatory mediators in the body, both of which are detrimental to cognitive function [12]. Research has shown a reciprocal relationship between sleep disorders and inflammation [13]. A neuroinflammatory process is responsible for cognitive impairment and various neurodegenerative diseases [14]. Activation of toll-like receptor-4 (TLR-4) by lipopolysaccharide (LPS) leads to transcription of pro-inflammatory factors from nuclear factor kappa B (NF-kB) and activating protein 1 (AP1) [15]. The hippocampus is sensitive and vulnerable to inflammation [16]. Some studies have shown that LPS injection impairs spatial learning and memory in the MWM test and increases levels of inflammatory cytokines in the hippocampus, including tumor necrosis factor-α (TNF-α), AP1, interleukin (IL)-6, and IL-1β [17, 18]. New evidence has shown that cytokines, previously considered only inflammatory substances produced in the brain, are critical for synapse development and function [19, 20].

Concerning neuroinflammatory consequences associated with SD and the interplay between SD, brain inflammation triggered by LPS, and their consequences on learning, memory, and LTP, the present study aimed to explore the synergistic effects of SD and LPS-induced inflammation on spatial learning, memory, and LTP in male rats.

Animals, Drugs, and Study Design

The subjects examined in this research included male Wistar rats weighing 200–250 g (n = 70). The animals were kept in a 12-h light-dark cycle, 60 ± 5% humidity, and at 23 ± 2°C. The animals always had ad libitum access to food and water. The food pellets were purchased from the Iran-made Pars Animal Feed Company. The experimental methods were performed following the standards for the care of experimental animals approved by the Ethics Committee of Kerman Neuroscience Research Center (ethics code: EC/KNRC/9947) and Mashhad University of Medical Sciences (IR.MUMS.REC.1402.135).

The experiments were conducted in two parts: behavioral and electrophysiological assessments. Subsequently, the brains of the rats from the behavioral study were collected for biochemical analysis.

In the behavioral study, the animals were divided into six groups as follows: (1) wide platform (WP) group: rats were placed on a WP for 24 h, followed by MWM on the next day; (2) SD group: the rats were sleep-deprived for 24 h using a small platform and underwent MWM on the subsequent day; (3) Saline group: the rats received a saline injection (1 mL/kg) for 7 days, and MWM was performed on the 8th day; (4) and (5) LPS1 and LPS2 groups: rats received daily intraperitoneal (i.p.) injections of LPS (1 or 2 mg/kg, respectively) for 7 days, and MWM was conducted on the 8th day; and (6) LPS1+SD group: rats received daily LPS injections (1 mg/kg i.p.) for 7 days, subjected to 24 h of SD using the small platform on the 7th day, and underwent MWM on the 8th day. The experimental design is depicted in Figure 1. The tests were performed between 10:00 a.m. and 2:00 p.m.

Fig. 1.

Experimental design: following a 7-day i.p. administration of LPS, the LPS1+SD group underwent SD for 24 h, in contrast, the Saline group and LPS1 group received saline or LPS1 mg/kg injections for 7 days, respectively. The next day, all groups were prepared for MWM, ELISA, and electrophysiological experiments. Additionally, 24 h prior to the commencement of the experiments, the SD and WP groups were placed on small and large platforms, respectively (the tests were performed at 10:00 a.m. to 2:00 p.m.) (D, day; h, hour; LPS, lipopolysaccharide; SD, sleep deprivation; i.p., intraperitoneal; WP, wide platform; MWM, Morris water maze; ELISA, enzyme-linked immunosorbent assay).

Fig. 1.

Experimental design: following a 7-day i.p. administration of LPS, the LPS1+SD group underwent SD for 24 h, in contrast, the Saline group and LPS1 group received saline or LPS1 mg/kg injections for 7 days, respectively. The next day, all groups were prepared for MWM, ELISA, and electrophysiological experiments. Additionally, 24 h prior to the commencement of the experiments, the SD and WP groups were placed on small and large platforms, respectively (the tests were performed at 10:00 a.m. to 2:00 p.m.) (D, day; h, hour; LPS, lipopolysaccharide; SD, sleep deprivation; i.p., intraperitoneal; WP, wide platform; MWM, Morris water maze; ELISA, enzyme-linked immunosorbent assay).

Close modal

The adverse effects of LPS on cognitive functions were assessed by administrating 1 or 2 mg/kg of LPS, followed by MWM testing and comparing rats’ behavior between the two groups. For this comparative analysis, 6 rats were introduced in the LPS2 group and were subsequently compared with 6 rats from the Saline and LPS1 groups.

The group in which LPS1 did not exhibit a significant effect was selected for the following study. LPS (E. coli 055: B5) was purchased from Sigma (Sigma-Aldrich Chemical Co.) and dissolved in saline. The hippocampus of four groups (Saline, SD, LPS1, and LPS1+SD) was removed for enzyme-linked immunosorbent assay (ELISA). The other experimental next set of rats was used for the electrophysiological study. The rats were divided into four groups, namely, Saline, SD, LPS1, and LPS1+SD.

Induction of SD

The method used in this study was similar to previous reports (5–8). SD was induced using a multiple-platform apparatus. This SD apparatus was created according to standard references in the Kerman Neuroscience Research Center. The apparatus had dimensions of 90 cm × 50 cm × 50 cm. It contained 10 columns, each 10 cm high and 7 cm in diameter, placed 2 cm above the water surface. The columns were arranged in two rows, placed 10 cm apart, to allow rats to jump from one platform to another. Social stability was maintained by housing 4 rats together in a chamber with clean water bottles and food pellet baskets hanging at the top. In this study, SD was induced for 24 h. Behavioral and electrophysiological assessments were performed immediately following the 24-h period of SD. We also examined at the possible effects of new environmental stress by putting control rats in a similar chamber with WP (15 cm in diameter and 10 cm in height). Note that the WP was wide enough for the rats to sleep on without falling into the water [7, 8].

MWM Test

A circular pool with a 160 cm diameter and an 80 cm height was filled with water to a depth of 40 cm. The water temperature was set at 25 ± 2°C. The inner wall of the pool was black. It was checked regularly and filled with colorless water. The pool was divided hypothetically into four quadrants of equal size. A square platform (10 cm) was concealed 1.5 cm below the water’s surface in the middle of the northeast quadrant. The walls around the maze were covered with more geometric images, and a dim light was provided for the room. A video tracking system (Noldus EthoVision VR system, version 7.1, The Netherlands) was used to capture the behavior [21].

The MWM test was completed in a single day. The training period included three blocks separated by a 30-min rest break. There were four trials in each block. In each trial, the rats were released from one of the predetermined locations (North, South, East, and West). Each of these four trials lasted 60 s, with a 60-s inter-trial gap. The platform’s placement remained constant during training, and rats were allowed to swim to the hidden escape platform within the 60-s period. If the animal located the platform, it was permitted to stay on it for 20–30 s. The time and distance required to locate the concealed platform were gathered [21]. Two hours after the training period, a 60-s probe trial was conducted to assess spatial memory. Afterward, the time and distance spent in the target quadrant (the quadrant where the platform was located during the training phase) were recorded. After the probe trial, a visual test was conducted to evaluate the potential impact of sensory and motor coordination or motivation on performance. This test evaluated the rats’ ability to escape to a visible platform by placing an aluminum foil-covered platform 2 cm above the water [21].

ELISA

Low-pressure CO2 flow in a desiccator jar was used to sacrifice the animals used in the MWM test. After decapitation, 0.1 g of the hippocampi was separated on an ice-cold surface and frozen in liquid nitrogen. The hippocampal tissues were weighed and homogenized in ice-cold 1 mL of RIPA buffer (Karmania Pars Gene, Kerman, Iran) containing protease inhibitors using a tissue homogenizer (Silent Crusher S Homogenizer, Germany). The resulting homogenates (10% W/V) were centrifuged at 14,000 rpm for 15 min at 4°C. However, in the higher concentrations of proteins than the top standard (200 pg/mL) in the hippocampus, the samples need to be diluted. Finally, 50 μL of each sample was used for analysis.

Specific rat ELISA kits (tumor necrosis factor alpha (TNF-α): KPG-RTNF; interleukin-1β (IL-1β): KPG-RIL1βP, interleukin-6 (IL-6): KPG-RIL6P) were used for the ELISA analysis. Their detection limit was 5–200 pg/mL for all kits. The manufacturer’s instructions were followed, and the samples’ absorbance and standards were read at wavelengths of 450 and 570 nm. Finally, the values of 570 nm were subtracted from those of 450 nm, the data were analyzed, and concentrations of TNF-α, IL-1β, and IL-6 were calculated.

Electrophysiology Study

Twenty-four rats were used for this part of the study. The groups consisted of Saline, SD, LPS1, and LPS1+SD. The cornu ammonis region (CA1) of the hippocampus was used for the experiments for in vivo electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) [22]. Rats were anesthetized with urethane (1.2 g/kg i.p., Sigma-Aldrich, USA) and placed in a stereotaxic device. The urethane is a great analgesia that provides prolonged and relatively stable anesthesia in rats [23]. The rats’ body temperature was maintained at 37 ± 0.5°C for electrophysiological recordings (Harvard Apparatus). After assessing the tail pinch response, the anesthesia degree was maintained by further injections of anesthetics (10% of the first dose), if necessary. After the animals had undergone a profound state of anesthesia by urethane, the administration of lidocaine local anesthesia was initiated prior to the commencement of the surgical procedure. Two holes were drilled after exposure of the skull, and the stimulation and recording electrodes were placed in a sterile environment according to the atlas of Paxinos and Watson (2006). A concentric bipolar stimulating electrode (stainless-steel, 0.125 mm diameter; Advent, UK) was placed in the Schaffer collateral pathway (DV = 2.8–3 mm; AP = 3 mm; ML = 3.5 mm) [9, 21], and a stainless-steel recording electrode was lowered into the stratum radiatum of the CA1 area of the right hippocampus (AP = 4.1; ML = 3 mm; AP = 2.5). The stimulating electrode was coupled to a stimulator, while the recording electrode was connected to an amplifier. We generated an input-output (I-O) curve by gradually increasing the stimulus intensity at constant current (input) and monitoring the fEPSP (output) after a 30-min stabilization period. Extracellular field potentials were amplified and filtered (1 Hz–3 kHz band pass) using a differential amplifier. A baseline was established by administering a test stimulus every 10 s for 20 min at the stimulus intensity at which 50% of the maximal response was required. Before LTP testing, rats underwent paired-pulse ratio (PPR). This facilitation was assessed by delivering ten consecutive responses of paired pulses with 20 ms, 50 ms, 70 ms, 100 ms, and 150 ms inter-pulse interval (10 s interval) to the Schafer-collaterals (SC) pathway. At different inter-stimulus intervals, the slope ratio of fEPSP was measured as second fEPSP slope/first fEPSP slope, fEPSP2/fEPSP1. LTP was measured by administrating high-frequency stimuli (HFS: 10 pulses at 400 Hz/7 s, repeated for 70 s). Next, administration of a test stimulus was determined every 10 s for 2 h after HFS the maintenance of LTP. The slope values of fEPSP at each time point in the graphs were calculated by averaging the slope values of 10 consecutive traces. Simulation and recording were performed using Neurotrace software (version 9) and Electromodule 12 on computer (Science Beam Institute, Tehran, Iran). Potentialize program from the same institute was used to analyze the responses [9]. Finally, low-pressure CO2 flow in a desiccator jar was used to sacrifice the animals that were used in the electrophysiological study.

Statistical Analysis

The data were expressed as the mean ± standard error of the means (SEMs). Normal distribution was checked using the Shapiro-Wilk test. Since the parameters had a normal distribution, parametric statistics were applied. Repeated-measures two-way analysis of variance (ANOVA) was used to assess the differences in learning between groups in the MWM test (with groups and blocks as the variables) and the overall differences in LTP time points (with group and time as the factors). The MWM probe experiment results and the biochemical data were evaluated using a one-way ANOVA. If there was a significant difference between the groups, Tukey’s post hoc multiple comparisons were performed. Differences between the groups were considered significant at p < 0.05. Statistical analyses were performed using the GraphPad Prism software (ver. 8.4.3).

MWM Test

The total distance in the Saline group was 888.9 ± 42.7, 622.4 ± 27.2, and 415.5 ± 21.8 cm in the block 1, block 2, and block 3, respectively. In the LPS1 group, the total distance was 1,019.2 ± 119.1 cm in the block 1, 665.1 ± 122.4 cm in the block 2, and 427.4 ± 130.4 cm in the block 3. The total distance in the block 1, block 2, and block 3 was 1,198.1 ± 30.3, 922 ± 57.2, and 819.5 ± 120 cm, respectively, in the LPS2 group (Fig. 2a). The repeated-measures two-way ANOVA showed significant differences between groups during the acquisition phase of the MWM test. Total distance was greater in the LPS2 group compared to the Saline group (block 1: p < 0.001, block 2: p < 0.01, block 3: p < 0.05) (Fig. 2a). Also, the escape latency in the learning phase for the Saline group was 37.7 ± 2.1 s in the block 1, 33.4 ± 2.8 s in the block 2, and 27.3 ± 3.3 s in the block 3. In the LPS1 group, the escape latency was 44 ± 5.4 s, 29.4 ± 5.7 s, and 21.4 ± 6 s in the block 1, block 2, and block 3, respectively. The escape latency in the block 1, block 2, and block 3 was 42.6 ± 1.9 s, 39.1 ± 4.7 s, and 47.8 ± 2.2 s (Fig. 2b). The two-way repeated-measures test (ANOVA) revealed significant differences between groups in escape latency. In block 3 of the learning phase, escape latency was higher in the LPS2 group than in the Saline group on block 3 (p < 0.01). In addition, there was higher in the LPS2 group compared to the LPS1 group in block 3 of the learning phase (p < 0.05) (Fig. 2b).

Fig. 2.

To compare the total distance (a) and escape latency (b) for finding the platform during three learning blocks, the distance percentage in the target quadrant (c), and time percentage in the target quadrant (d) during the probe test among groups receiving saline, LPS injection 1 mg/kg (LPS1) and 2 mg/kg (LPS2). The data are presented as mean ± standard error of the mean (SEM) (*/#p < 0.05, **p < 0.01, ***p < 0.001, *compared to the Saline group and # compared to the LPS1 group) (LPS1, lipopolysaccharide 1 mg/kg; LPS2, lipopolysaccharide 2 mg/kg) (n = 6).

Fig. 2.

To compare the total distance (a) and escape latency (b) for finding the platform during three learning blocks, the distance percentage in the target quadrant (c), and time percentage in the target quadrant (d) during the probe test among groups receiving saline, LPS injection 1 mg/kg (LPS1) and 2 mg/kg (LPS2). The data are presented as mean ± standard error of the mean (SEM) (*/#p < 0.05, **p < 0.01, ***p < 0.001, *compared to the Saline group and # compared to the LPS1 group) (LPS1, lipopolysaccharide 1 mg/kg; LPS2, lipopolysaccharide 2 mg/kg) (n = 6).

Close modal

The probe test was used to evaluate spatial memory performance. This test analyzed the mean percentage of distance traveled and time spent in the target quadrant. The percentage of distance traveled in the target zone in the Saline, LPS1, and LPS2 groups were 39.95 ± 2.36, 34.24 ± 3.92, and 30.22 ± 4.1, respectively. The one-way ANOVA indicated that there was no difference in the percentage of distance traveled in the target zone. Meanwhile, these percentages were 44.03 ± 2.32 and 34.82 ± 4.52 in the Saline and LPS1 groups, respectively, and decreased in the LPS2 group (21.2 ± 1.89). The percentage of escape latency in the target quadrant decreased in the LPS2 group compared to the Saline group (p < 0.001) and was lower in the LPS2 group compared to the LPS1 group (Fig. 2c, d).

Total distance in the learning phase for the Saline group was 860 ± 39.4 cm in block 1, 642.8 ± 60.9 cm in block 2, and 432.3 ± 20.3 cm in block 3. In the WP group, total distance was 708.7 ± 8.4, 522.8 ± 39.4, 440.2 ± 67 cm in blocks 1, 2, and 3, respectively. In the SD group, the total distance was 1,028.6 ± 115.9 cm in block 1, 699.5 ± 109.3 cm in block 2, and 378 ± 46.6 cm in block 3. Total distance was 979.5 ± 105.1 cm in block 1, 580.6 ± 105.4 cm in block 2, and 381.2 ± 100.9 cm in block 3 in the LPS1 group. Also, the total distance for the LPS1+SD group was 1,471.5 ± 48.9 cm, 1,196.7 ± 77.2 cm, and 1,109.8 ± 102.9 cm in block 1, 2, and 3, respectively (Fig. 3a). Total distance increased in the LPS1+SD group compared to the Saline group (block 1: p < 0.001, block 2: p < 0.001, block 3: p < 0.01), SD group (block 1: p < 0.05, block 2: p < 0.05, block 3: p < 0.001), and LPS1 group (block 1: p < 0.05, block 2: p < 0.001, block 3: p < 0.001) (Fig. 3a). Escape latency in the Saline group was 36.6 ± 2.5 s in block 1, 33.3 ± 2.2 s in block 2, and 25.9 ± 2.6 s in block 3. In the WP group, escape latency was 24.5 ± 3.1 s, 19.3 ± 1 s, and 18.5 ± 2.6 s in block 1, block 2, and block 3, respectively. In the SD group, the escape latency was 38.7 ± 5.1 s in block 1, 29 ± 3.6 s in block 2, and 20 ± 1.4 s in block 3. Escape latency was 41.2 ± 5 s in block 1, 25.7 ± 4.8 s in block 2, and 19 ± 4.7 s in block 3 in the LPS1 group. Also, the escape latency in the learning phase for the LPS1+SD group was 52.2 ± 1.2 s in the block 1, 43.1 ± 2.5 s in the block 2, and 38.2 ± 1.3 s in the block 3 (Fig. 3b). There was higher escape latency in the LPS1+SD group compared to the Saline group of the learning phase (block 1: p < 0.01, block 2: p < 0.05, and block 3: p < 0.05). In addition, there was higher escape latency in the LPS1+SD group compared to the SD group on block 2 (p < 0.05) and block 3 (p < 0.001) and the LPS1 group on block 3 of the learning phase (p < 0.05) (Fig. 3b). Distance traveled in the target quadrant in the Saline, WP, SD, and LPS1 groups was 40.57 ± 1.77, 36.11 ± 4.27, 37.76 ± 1.67, and 36.34 ± 3.845 cm, respectively, while it decreased in LPS1+SD group (26.28 ± 1.89 cm). Distance traveled in the target quadrant decreased in the LPS1+SD group compared to the Saline group (p < 0.05), but the time spent in the target zone showed no significant difference with other groups. These values in the Saline, WP, SD, LPS1, and LPS1+SD groups were 43.65 ± 1.76, 33.43 ± 5.19, 35.04 ± 2.08, 36.76 ± 4.34, and 29.94 ± 2.8, respectively (Fig. 3c, d).

Fig. 3.

Combined effects of LPS and SD on learning and memory in the MWM. Comparison of total distance (a) and escape latency (b) to locate the platform over three learning blocks, percentage of distance moved in the target quadrant (c), and the percentage of total time spent in the target quadrant (d) during probe trials among the Saline, WP, SD, LPS, and LPS1+SD groups. The data are presented as mean ± standard error of the mean (SEM) (٭/#p < 0.05, ٭٭/##p < 0.01, ٭٭٭/###p < 0.001, ٭compared to the Saline and #compared to the LPS and SD groups) (MWM, Morris water maze; WP, wide platform; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 8).

Fig. 3.

Combined effects of LPS and SD on learning and memory in the MWM. Comparison of total distance (a) and escape latency (b) to locate the platform over three learning blocks, percentage of distance moved in the target quadrant (c), and the percentage of total time spent in the target quadrant (d) during probe trials among the Saline, WP, SD, LPS, and LPS1+SD groups. The data are presented as mean ± standard error of the mean (SEM) (٭/#p < 0.05, ٭٭/##p < 0.01, ٭٭٭/###p < 0.001, ٭compared to the Saline and #compared to the LPS and SD groups) (MWM, Morris water maze; WP, wide platform; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 8).

Close modal

There was no significant difference between the experimental groups’ swimming speed and latency to find the visible platform. Therefore, the intervention did not cause any motor or sensory deficits in the trial animals (Table 1).

Table 1.

Velocity and visible test data

GroupsVelocity, cm/sTime to find the platform, s
Saline 25.2±0.98 15.1±2.9 
SD 23.4±0.95 13.5±2.6 
WP 25.8±0.55 11.5±1.6 
LPS1 22.9±1.31 11.2±3.6 
LPS1+SD 22.6±0.75 14±2.6 
GroupsVelocity, cm/sTime to find the platform, s
Saline 25.2±0.98 15.1±2.9 
SD 23.4±0.95 13.5±2.6 
WP 25.8±0.55 11.5±1.6 
LPS1 22.9±1.31 11.2±3.6 
LPS1+SD 22.6±0.75 14±2.6 

ELISA

TNF-α in the Saline, SD, LPS1, and LPS1+SD groups were 52.56 ± 6.68, 54.96 ± 3.68, 57.2 ± 6.56, and 64.79 ± 4.97 pg/mL, respectively. After the ELISA test, one-way ANOVA indicated no significant difference in the TNF-α level of experimental groups (Fig. 4a). IL-1β in the Saline, SD, and LPS1 groups were 28.65 ± 3.5, 33.79 ± 2.03, and 38.33 ± 5.79 pg/mL, respectively, while it increased in the LPS1+SD group (43.41 ± 1.15 pg/mL). The hippocampal levels of IL-1β in the LPS1+SD group were significantly higher than in the Saline group (p < 0.05) (Fig. 4b). The hippocampal IL-6 levels in the Saline, SD, LPS1, and LPS1+SD groups were 75.29 ± 3.7, 68.11 ± 2.81, 95.33 ± 2.813, and 87.12 ± 6.06 pg/mL, respectively. IL-6 in the LPS1 group was significantly more than in the Saline group (p < 0.05). Moreover, IL-6 in the LPS1+SD group was higher than in the SD group (p < 0.05) (Fig. 4c).

Fig. 4.

Comparison of the hippocampal level of TNF-α (a), IL-1β (b), and IL-6 (c) between the Saline, SD, LPS, and LPS1+SD groups. The data are presented as mean ± standard error of the mean (SEM) (٭/#p < 0.05, ٭compared to the Saline and # compared to the SD group) (TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Fig. 4.

Comparison of the hippocampal level of TNF-α (a), IL-1β (b), and IL-6 (c) between the Saline, SD, LPS, and LPS1+SD groups. The data are presented as mean ± standard error of the mean (SEM) (٭/#p < 0.05, ٭compared to the Saline and # compared to the SD group) (TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Close modal

LTP

LTP induction in the CA1 region of the dorsal hippocampus was confirmed by a significant increase in the fEPSP slope (more than 20%). Also, maintenance of LTP was assessed by measuring fEPSP for 2 h after high-frequency stimulation (HFS). In the field potential recording, we applied 1 mg/kg LPS for 7 days accompanied by 24 h SD, similar to the MWM test. The results showed that the fEPSP slope decreased in the LPS1+SD group compared with the Saline group (p < 0.05). HFS applied to the SC pathway of the dorsal hippocampus CA1 area caused LTP of the fEPSP slope in the SD group. During the maintenance phase, the SD group had lower fEPSP slopes than the Saline group. The repeated-measure two-way ANOVA followed by Tukey᾿s post hoc test after HFS demonstrated LTP induction in the LPS1 group. During the maintenance phase, the LPS1 group had a lower fEPSP slope than the Saline group. The administration of LPS1 combined with SD reduced the ability of LTP induction in the neuronal circuits of the rat hippocampus, resulting in a significant decrease in LTP induction in the LPS1+SD group compared to the Saline group (p < 0.05). During the maintenance phase, the fEPSP slopes in the LPS1+SD group were lower than in the Saline group (Fig. 5b). The fEPSP slopes in the Saline, SD, and LPS1 groups were 150.7 ± 5.94, 132.5 ± 4.92, and 129.1 ± 4.27 min, respectively, while it decreased in the LPS1+SD group (105.6 ± 1.1 min).

Fig. 5.

Effects of LPS and SD on LTP in the CA1 region of the hippocampus in rats. a Sample record of fEPSP recordings across the Saline, SD, LPS, and LPS1+SD groups. b Comparing the induction and maintenance of LTP among all groups The data are presented as mean ± standard error of the mean (SEM) (٭p < 0.05, ٭٭p < 0.01, ٭٭٭p < 0.001, ٭compared to the Saline group) (LTP, long-term potentiation; CA1, cornu ammonis region 1; HFS, high-frequency stimuli; SD, sleep deprivation; fEPSP, field excitatory postsynaptic potentials; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Fig. 5.

Effects of LPS and SD on LTP in the CA1 region of the hippocampus in rats. a Sample record of fEPSP recordings across the Saline, SD, LPS, and LPS1+SD groups. b Comparing the induction and maintenance of LTP among all groups The data are presented as mean ± standard error of the mean (SEM) (٭p < 0.05, ٭٭p < 0.01, ٭٭٭p < 0.001, ٭compared to the Saline group) (LTP, long-term potentiation; CA1, cornu ammonis region 1; HFS, high-frequency stimuli; SD, sleep deprivation; fEPSP, field excitatory postsynaptic potentials; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Close modal

I-O curves versus increasing stimulus intensity were plotted to examine changes in the slope of the fEPSP as a function of LPS1, SD, and LPS1+SD. Overall, the rats showed no significant difference in the input/output relationship (Fig. 6a). I-O is equal to 243.2 ± 16.54 micro-amperes (µ-amp) in the Saline group, 204.4 ± 7.53 µ-amp in the SD group, 155.1 ± 9.65 µ-amp in the LPS1 group, and 207.9 ± 3.48 µ-amp in the LPS1+SD group. The PPR was also not significantly different between groups (Fig. 6b). PPR in the Saline, SD, LPS1, and LPS1+SD groups was 1.63 ± 0.06, 1.47 ± 0.1, 1.32 ± 0.06 ms, and 1.495 ± 0.02 ms, respectively.

Fig. 6.

a I-O curves were generated based on the slope of fEPSP in response to various stimulus intensities in the CA1 region of the hippocampus among the Saline, SD, LPS, and LPS1+SD groups. b Similarly, comparison of the PPR among all groups. Data are presented as mean ± standard error of the mean (SEM) (I-O, input-output; fEPSP: field excitatory postsynaptic potentials; PPR, paired-pulse ratio; CA1, cornu ammonis region 1; mv, millivolt; ms, millisecond; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Fig. 6.

a I-O curves were generated based on the slope of fEPSP in response to various stimulus intensities in the CA1 region of the hippocampus among the Saline, SD, LPS, and LPS1+SD groups. b Similarly, comparison of the PPR among all groups. Data are presented as mean ± standard error of the mean (SEM) (I-O, input-output; fEPSP: field excitatory postsynaptic potentials; PPR, paired-pulse ratio; CA1, cornu ammonis region 1; mv, millivolt; ms, millisecond; SD, sleep deprivation; LPS1, lipopolysaccharide 1 mg/kg) (n = 6).

Close modal

The present study investigates the interacting effects of SD on LPS-induced brain inflammatory response, spatial learning and memory, and LTP in male rats. Our results showed that LPS1 impaired spatial learning and memory in sleep-deprived rats in the MWM test. Also, LPS1, together with SD, decreased the magnitude of hippocampal LTP at CA3–CA1 synapses in male rats. Moreover, the IL-1β level was significantly increased in LPS1+SD-exposed rats.

The MWM test was used to evaluate spatial learning and memory in current study. In the first phase, the effects of two doses (1 and 2 mg/kg) of LPS on spatial learning and memory were investigated. The results revealed that LPS (2 mg/kg/7 days) increased total distance and escape latency in this group compared to the Saline group in the learning phase. Moreover, in the memory phase, the time spent in the target quadrant decreased in this group compared to the Saline group, but LPS 1 mg/kg/7 days had no similar effect. The tolerance mechanism is an adaptive crucial event in preventing endotoxic shock [22] which may elucidate the results of present study. In addition, it is suggested that LPS-induced cognitive impairment is dose-dependent [24]. Other studies on the dose-dependent effect of LPS found that different doses of LPS activate different pathways [25, 26]. In another study, Zhu et al. [27] found that administering LPS for 7 days significantly increased latency to the platform and decreased the time spent in the target quadrant during the MWM test compared to administering LPS for 3 days. Another study showed that repeated peripheral exposure to LPS does not significantly affect corticosterone levels, while acute injection of LPS elevated corticosterone [28]. Through using LPS in rodents, neuroinflammation plays an important role in brain disorders [26]. Several investigations have demonstrated the SD’s detrimental impacts on cognitive functioning at various time intervals. The adverse cognitive consequences of SD for 48 h and 72 h have been observed in experimental rat models [5, 29, 30]. Subsequently, the effects of SD on the performance of rats exposed to 1 mg/kg of LPS for 7 days were investigated in the MWM test. The results showed that total distance and escape latency increased in the LPS1+SD group compared to the Saline group. Besides, in the memory phase, the distance traveled in the target quadrant decreased in the LPS1+SD group compared to the Saline group. Likewise, our previous studies on corticosterone showed that environmental condition does not affect corticosterone; the explanation is that no significant difference was observed between the SD and WP groups [5, 31]. Also, the method of multiple platforms eliminates the stress of isolation and immobility compared to other SD methods [6]. Indeed, we showed that co-administration of SD and LPS was more effective than SD and LPS separately on cognitive impairment.

The synaptic basis of learning and memory in vertebrates is studied using LTP induction as an experimental model [32]. Short stimulations and high-frequency training of the hippocampal pathway lead to long-term increases in response to experimental stimuli [32]. The SC pathway in CA1 of the hippocampus has been frequently studied for LTP [33]. LPS administration impairs LTP induction in the hippocampus of rats [34]. Our behavioral results were confirmed by fEPSP recording. The present study showed that the fEPSP slope in the LPS1+SD group was lower than that in the Saline, SD, and LPS1 groups. These negative effects on hippocampal neuroplasticity may be due to inflammatory signals inhibiting neural stem cell proliferation, increasing apoptosis of neural progenitor cells, and decreasing newly developed neurons’ survival and their integration into existing neural circuits [35]. Excessive activation of the immune system has been shown to impair various aspects of hippocampal functioning. Meanwhile, normal and quiescent conditions promote remodeling neuronal circuits underlying neuroplasticity, LTP, and neurogenesis in the hippocampus [19]. The effects of SD on LTP induction [8, 36] have been studied in durations of 24 [6], 48 [5], and 72 h SD [7, 37]. Indeed, fEPSP recording confirmed our behavioral findings, demonstrating that stimulation of the SC pathway caused LTP in all individuals except the LPS1+SD group. In contrast, LPS1+SD reduced the induction of LTP postsynaptically with a significant effect on the maintenance phase without affecting presynaptic neurotransmitter release.

The effect of LPS and SD on basal synaptic performance was evaluated using I-O curves to plot changes in the slope of the fEPSP against increasing stimulus intensities. Overall, no significant difference in the input/output relationship was observed between all rats (Fig. 6a). Furthermore, we aimed to investigate whether presynaptic mechanisms contributed to the effects of SD or LPS1 on synaptic plasticity, as reflected in the measurement of PPR values. The results revealed that PPR values remained unaffected in the experimental groups (Fig. 6b). It means the I-O curve, which is the change in the fEPSP slope in response to stimulation intensity, was drawn to investigate the effects of SD and brain inflammatory response on basic synaptic transmission. Statistical analysis showed that the basic synaptic transmission is potentiated in all the groups, which was determined by the increase in the fEPSP slope. Therefore, the synaptic potentiation in these groups is similar to the Saline group, and our treatments do not affect the neurons’ excitability. Presynaptic facilitation curve was drawn to investigate the effects of SD and brain inflammatory response on baseline presynaptic facilitation. Statistical analysis showed a lack of any difference in the release of the presynaptic neurotransmitter glutamate among the groups, which was determined by the lack of significant differences in the changes in the PPR in the groups. In fact, glutamate release does not affect the postsynaptic function and LTP induction. It is revealed that SD and LPS1 treatments caused significant changes in the postsynaptic potential. Consistent with previous studies, our findings demonstrate that neither the I-O curve nor PPRs exhibited alterations across the groups. This observation can be attributed to the absence of changes in the probability of neurotransmitter release from hippocampal presynaptic terminals under the specific experimental conditions employed [9, 21].

LPS administration impaired LTP induction in rats’ hippocampus, which was reflected by decreasing amplitude and fEPSP slope in the LPS group compared to the Saline group [18, 34]. Some studies have shown that SD significantly disrupted LTP [5, 8, 9]. One of the most prevalent techniques for causing an inflammatory animal model is using LPS [38]. LPS regularly promotes TLR-4-mediated production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [39, 40]. By binding to TLR-4, LPS activates nuclear factor kappa B (NF-κB) [15]. The transcription factor NF-κB mediates inflammatory responses by regulating pro-inflammatory cytokines [41], which are responsible for the upregulation of inflammatory cytokines such as IL-1β, activating protein (AP1), and prostaglandin E2 [15, 42].

In addition, SD has been shown to increase the production of pro-inflammatory and decrease anti-inflammatory cytokines [43]. The study found a correlation between increased levels of IL-1β and IL-6 in both the hippocampus and plasma and impairments in spatial memory. This correlation indicates that neuroinflammation may be responsible for the deficits in spatial learning and memory induced by SD [43]. These findings are consistent with the observation that the adverse effects of SD on hippocampal neurogenesis can be mitigated by blocking microglial activation with an anti-inflammatory drug [44]. The release of pro-inflammatory molecules can damage synaptic connections, lead to neuronal death, and inhibit neurogenesis [45]. The results of this study showed that 24 h SD did not increase IL-1β concentration in the hippocampus. Interestingly, SD impacted the effect of LPS, and IL-1β was significantly increased in the LPS1+SD group compared with the Saline group. In addition, IL-6 was significantly increased in the hippocampus of the LPS1 group compared to the Saline group, and it was significantly upregulated in the LPS1+SD group compared with the SD group. The results showed no difference in the IL-6 between the LPS1+SD group and the LPS1 group. These results might be related to the sleep cycle [46] and sampling time [47]. TNF-α results showed no significant difference between groups. In this study, the ELISA method was applied as a highly sensitive and accurate technique [48]. Nevertheless, using more precise molecular techniques like RT-qPCR might provide better outputs. In addition, reduced production of cytokines in vivo after repeated exposure to LPS in short intervals appears to be a common occurrence [49]. It was previously reported that daily injections of LPS in rats caused a significant increase in the release of TNF-α, IL-1β, and IL-6 after the first injection, although this effect was eliminated afterward [22]. However, the results of the present study might be due to tolerance to the LPS injection. It has been demonstrated that differential transcription factor plays a role in selective gene expression during LPS tolerance. There is a shift in NF-kB complex composition after LPS stimulation, with naive cells showing p65/p50 heterodimers inducing strong gene transcription, while tolerized cells mainly exhibit p50/p50 homodimers, lacking transcriptional activity [50]. Hence, it needs to be further investigated. The TNF-α ELISA results in our study were consistent with those of Brianza-Padilla et al. [51] who showed that different SD periods from 24 to 192 h did not affect serum levels of TNF-α. Their results showed an increase in the serum level of IL-6 but no change in the TNF-α level. They related this result to the scenario that IL -6, with its anti-inflammatory effect, prevents the increase in the TNF-α level and thus prevents inflammation after SD. However, we observed a change in IL-6 levels in the LPS1 group compared with the Saline group and in the LPS1+SD group compared with the SD group [51]. It has also been reported that TNF-α does not play an essential role in regular learning or memory consolidation [20]. Therefore, to more accurately relate the SD-induced learning and memory impairments in the LPS1+SD group to the neuroinflammation induced by LPS1 injection and SD, it is necessary to investigate the changes in TNF-B expression in future studies [20]. In addition, meta-analysis studies revealed that different parts of the brain respond differently to SD [52].

In addition to a healthy immune system, healthy sleep is also important for forming spatial learning and memory [53]. Multiple studies have demonstrated sleep’s essential effect on the brain for learning, memory, and cognition processes [43, 53]. Multiple signaling pathways are thought to be facilitated by sleep, making spatial memory processes easier [53‒55]. Sleep disturbance impairs several brain functions [56], including learning and memory [57]. Many events, including oxidative stress, inflammation, and glial dysfunction, may aggravate sleep disorders [58]. Generally, inflammatory mechanisms aim to clear pathogenic cells [59]. Males and females can respond differently to identical environmental stimuli and experimental conditions [5]. Testosterone affects pathways of TNF-related apoptosis-inducing ligand (TRAIL) [59]. The immune response can interact with sex hormones like estrogen, progesterone, and testosterone, leading to differences in dimorphism between sexes in some neurodegenerative disorders [60]. Sex differences in the activation of components of inflammation require future studies.

Sleep disturbance and inflammation may share comparable molecular pathways to alter spatial memory operations [61]. According to these findings, the effects of the co-administration of SD and LPS1 for 7 days on the performance of the rats were examined in the MWM test. The results showed that experimental SD triggers inflammatory pathways at numerous physiologic levels in people [62]. According to previous study, sleep disturbance and inflammation are both associated with spatial memory impairments, and there is evidence that inflammation may act as a mediator between them [63]. In this respect, experimental and sleep disturbances and inflammatory states have been shown to affect spatial memory negatively. Hence, it is logical that the co-occurrence of sleep disturbances and inflammation creates a converging cycle that impairs spatial memory. This finding suggests that people with sleep disorders and high levels of inflammation are at higher risk of developing problems in their ability to remember the situations [63]. In line with previous studies, our findings showed that SD increased inflammatory cytokine in the hippocampus of the LPS1 group.

To summarize, the present study indicates that SD enhances the impact of brain inflammatory response induced by LPS1 on LTP and spatial learning and memory. This finding suggests that the combined effects of SD and brain inflammatory response may play a role in cognitive impairment through shared pathways.

We would like to thank the Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran, and the Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.

The research ethics codes are EC/KNRC/9947 and IR.MUMS.REC.1402.135. These codes have been approved by the Ethics Committee of the Kerman Neuroscience Research Center and Mashhad University of Medical Sciences, respectively.

The authors report that there are no competing interests to declare.

This study was supported by the contribution of the Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran (funding code: 4020688) and the Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran (funding code: 9947).

Maryam Salari designed the experiments, derived the models, analyzed the data, contributed to sample preparation, experimented, and wrote the manuscript with input from all authors. Khadijeh Esmaeilpour taught the experiments and reviewed the manuscript with input from all authors. Lily Mohammadipoor-Ghasemabad contributed to molecular sample preparation, performed the experiment, and consulted the analytic calculations. Farahnaz Taheri contributed to the field potential test and consulted the analytic calculations. Mahmoud Hosseini supervised the project and contributed to the interpretation of the results, review, and editing. Vahid Sheibani supervised the project and contributed to the interpretation of the results. All authors contributed to the final version of the manuscript, review, and editing. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding authors.

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