Karim A. Alkadhi

Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: Potential role of oxidative stress mechanisms

Our previous work suggests that pharmacological induction of oxidative stress causes anxiety-like behavior in rats. Interestingly, sleep deprivation is reported to cause oxidative damage in the brain and is also reported to be anxiogenic. Minimal mechanistic insights are available. In this study, using a behavioral and biochemical approach, we investigated involvement of oxidative stress mechanisms in sleep deprivation-induced anxiety-like behavior of rats and the protective role of treadmill exercise in this process. We report that acute sleep deprivation (SD) increases oxidative stress in the cortex, hippocampus and amygdala while prior treadmill exercise prevents this increase. Serum corticosterones also increase with SD but its levels are normalized in exercised sleep-deprived rats. Also, anxiety-like behavior of rats significantly increases with SD while prior treadmill exercise prevents this increase. Protein expression of two enzymes involved in antioxidant defense, glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 increased after 24h SD in the hippocampus, cortex and amygdala while their levels were normalized in exercised sleep-deprived rats. It is plausible that oxidative stress via regulation of GLO1 and GSR1 is involved in sleep deprivation-induced anxiety-like behavior of rats.

Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats

Both hypothyroidism and stress interfere with cognitive function in patients. This study examined the effect of hypothyroidism and stress on hippocampus-dependent learning and memory in rats using the novel radial arm water maze (RAWM), which measures spatial working memory. Hypothyroidism was accomplished by thyroidectomy and 2 weeks later a form of intruder stress was used as the chronic psychosocial stressor. After 4-6 weeks of stress, rats were trained to learn (during the acquisition phase; four trials) and then remember (during two memory test trials occurring 15 and 120 min after the acquisition phase) the within-day location of a hidden escape platform, which was in different arm every day. The number of errors (entry into arms other than the platform arm) was noted. Within-day learning of the platform location was largely unaffected by the experimental manipulations, indicating that rats in all groups were equally capable of finding the platform to escape from the water with similar numbers of errors (P > 0.005). The number of days a rat took to reach a criterion (DTC; a maximum of one error in three consecutive days) indicated that chronic stress or hypothyroidism, alone, resulted in a mild impairment of spatial memory, and the combination of chronic stress and hypothyroidism resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and hypothyroidism produced more deleterious effects on hippocampal function than either chronic stress or hypothyroidism alone.

Levothyroxin restores hypothyroidism-induced impairment of hippocampus-dependent learning and memory: Behavioral, electrophysiological, and molecular studies.

Hypothyroidism induces cognitive impairment in experimental animals and patients. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism‐induced learning and memory impairment. In this study, we investigated the effects of L‐thyroxin (thyroxin) treatment on hippocampus‐dependent learning and memory in thyroidectomized adult rats. In the radial arm water maze (RAWM) task, thyroxin treated thyroidectomized animals made significantly fewer errors than the untreated hypothyroid animals in Trial 3 of the acquisition phase, short‐term memory and long‐term memory tests. In addition, the number of errors made by the thyroxin treated thyroidectomized animals was not different from that of the control group. Furthermore, the days‐to‐criterion (DTC) values for thyroxin treated thyroidectomized animals were not different from those of the control group but significantly lower than those of the untreated hypothyroid animals. In anesthetized rats, extracellular recording from hippocampal area CA1 of hypothyroid rats shows that thyroxin treatment restores impaired Late‐phase long‐term potentiation (L‐LTP). Immunoblot analysis of signaling molecules, including cyclic‐AMP response element binding protein (CREB), mitogen‐activated protein kinases (MAPKp44/42; ERK1/2), in area CA1 revealed that thyroxin treatment reversed hypothyroidism‐induced reduction of signaling molecules essential for learning and memory, and L‐LTP. This study shows that thyroxin treatment reverses hypothyroidism‐induced impairment of hippocampus‐dependent cognition, and L‐LTP, probably by restoring the levels of signaling molecule important for these processes.

Chronic Psychosocial Stress Exacerbates Impairment of Cognition and Long-Term Potentiation in β-Amyloid Rat Model of Alzheimer's Disease

BACKGROUND Alzheimers disease (AD) is a degenerative disorder that leads to progressive cognitive decline. Alzheimers disease develops as a result of over-production and aggregation of beta-amyloid (Abeta) peptides in the brain. The reason for variation in the gravity of symptoms among AD patients is unknown and might result from patient-related factors including lifestyle. Individuals suffering from chronic stress are at an increased risk for developing AD. This study investigated the effect of chronic psychosocial stress in Abeta rat model of AD. METHODS Psychosocial stress was induced with a rat intruder model. The rat model of AD was induced by 14-day osmotic pump infusion of a mixture of 300 pmol/day Abeta(1-40)/Abeta(1-42). The effect of chronic stress on the severity of Abeta-induced spatial learning and memory impairment was tested by three approaches: behavioral testing in the radial arm water maze, in vivo electrophysiological recording in anesthetized rat, and immunoblot analysis to determine protein levels of learning- and memory-related molecules. RESULTS A marked impairment of learning and memory developed when stress was combined with Abeta, more so than that caused by Abeta alone. Additionally, there was a significantly greater impairment of early-phase long-term potentiation (E-LTP) in chronically stressed/Abeta-treated rats than in either the stressed or Abeta-treated rats. This might be a manifestation of the reduction in protein levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and the abnormal increase in calcineurin levels. CONCLUSIONS Chronic stress significantly intensified Abeta-induced deficits of short-term memory and E-LTP by a mechanism involving decreased CaMKII activation along with increased calcineurin levels.

Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF.

Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimers disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies.

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 microg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCgamma basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.

Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism.

Electrophysiological investigation of basal synaptic transmission and synaptic plasticity in the CA1 region of the hippocampus was carried out in anesthetized obese Zucker rats (OZR). Comparison of the input/output curves of basal field excitatory postsynaptic potential indicates that these are similar in both the OZR and its lean counterpart suggesting that basal synaptic transmission is intact in the OZR. However, high frequency stimulation evokes long-term potentiation (LTP) in the lean rat but not in the OZR. Since post-tetanic potentiation and paired pulse facilitation, forms of short-term potentiation of presynaptic origin, are also severely impaired in the OZR, the results imply that impairment of CA1 hippocampal LTP in these obese rats may be due, in part, to impaired presynaptic function. The results emphasize the potential deleterious effect of obesity on learning and memory functions of the CNS.

Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a condition which can develop from exposure to a severe traumatic event such as those occurring during wars or natural disasters. Benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are considered the gold standard for PTSD treatment, but their side effects pose a serious problem. While regular physical exercise is regarded as a mood elevator and known to enhance cognitive function, its direct role in rescuing core symptoms of PTSD including anxiety and depression-like behaviors and cognitive impairment is unclear. In the present study using the single-prolonged stress (SPS) rat model of PTSD (2h restrain, 20 min forced swimming, 15 min rest, and 1-2 min diethyl ether exposure), we examined the beneficial effect of moderate treadmill exercise on SPS-induced behavioral deficits including anxiety and depression-like behaviors and memory impairment. Male Wistar rats were randomly assigned into four groups: control (sedentary), exercised, SPS (no exercise), or SPS-exercised. Rats were exercised on a rodent treadmill for 14 consecutive days. Rats in all groups were tested for anxiety-like behaviors using open field (OF), light-dark and elevated-plus maze tests. All rats were tested for short-term and long-term memory in the radial arm water maze test. Rats were then sacrificed, blood was collected (for corticosterone levels), and individual organs (spleen, adrenals, and thymus) harvested. Results suggest that moderate physical exercise ameliorates SPS-induced behavioral deficits in rats.

Caffeine prevents sleep loss-induced deficits in long-term potentiation and related signaling molecules in the dentate gyrus

We have previously reported that caffeine prevented sleep deprivation‐induced impairment of long‐term potentiation (LTP) of area CA1 as well as hippocampus‐dependent learning and memory performance in the radial arm water maze. In this report we examined the impact of long‐term (4‐week) caffeine consumption (0.3 g/L in drinking water) on synaptic plasticity ( Alhaider et al., 2010 ) deficit in the dentate gyrus (DG) area of acutely sleep‐deprived rats. The sleep deprivation and caffeine/sleep deprivation groups were sleep‐deprived for 24 h by using the columns‐in‐water technique. We tested the effect of caffeine and/or sleep deprivation on LTP and measured the basal levels as well as stimulated levels of LTP‐related molecules in the DG. The results showed that chronic caffeine administration prevented the impairment of early‐phase LTP (E‐LTP) in the DG of sleep‐deprived rats. Additionally, chronic caffeine treatment prevented the sleep deprivation‐associated decreases in the basal levels of the phosphorylated calcium/calmodulin‐dependent protein kinase II (P‐CaMKII) and brain derived neurotrophic factor (BDNF) as well as in the stimulated levels of P‐CaMKII in the DG area. The results suggest that chronic use of caffeine prevented anomalous changes in the basal levels of P‐CaMKII and BDNF associated with sleep deprivation and as a result contributes to the revival of LTP in the DG region.