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.     

Caffeine treatment prevents rapid eye movement sleep deprivation‐induced impairment of late‐phase long‐term potentiation in the dentate gyrus

The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus, but they differ in various respects, including their reactions to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late‐phase long‐term potentiation (L‐LTP) and its signalling cascade in the DG area of the hippocampus of rapid eye movement sleep‐deprived rats. Rats were chronically treated with caffeine (300 mg/L drinking water) for 4 weeks, after which they were sleep‐deprived for 24 h. L‐LTP was induced in in anaesthetized rats, and extracellular field potentials from the DG area were recorded in vivo. The levels of L‐LTP‐related signalling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L‐LTP magnitude, and basal levels of total cAMP response element‐binding protein (CREB), phosphorylated CREB (P‐CREB), and calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented the reductions in the basal levels of P‐CREB, total CREB and CaMKIV in sleep‐deprived rats. Furthermore, caffeine prevented post‐L‐LTP sleep deprivation‐induced downregulation of P‐CREB and brain‐derived neurotrophic factor in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation‐induced deficits in brain function.     

Distinct modulatory effects of sleep on the maintenance of hippocampal and medial prefrontal cortex LTP

Both human and animal studies support the idea that memory consolidation of waking experiences occurs during sleep. In experimental models, rapid-eye-movement (REM) sleep has been shown to be necessary for cortical synaptic plasticity and for the acquisition of spatial and nonspatial memory. Because the hippocampus and medial prefrontal cortex (mPFC) play distinct and important roles in memory processing, we sought to determine the role of sleep in the maintenance of long-term potentiation (LTP) in the dentate gyrus (DG) and mPFC of freely behaving rats. Animals were implanted with stimulating and recording electrodes, either in the medial perforant path and DG or CA1 and mPFC, for the recording of field potentials. Following baseline recordings, LTP was induced and the animals were assigned to three different groups: REM sleep-deprived (REMD), total sleep-deprived (TSD) and control which were allowed to sleep (SLEEP). The deprivation protocol lasted for 4 h and the recordings were made during the first hour and at 5, 24 and 48 h following LTP induction. Our results show that REMD impaired the maintenance of late-phase (48-h) LTP in the DG, whereas it enhanced it in the mPFC. Sleep, therefore, could have distinct effects on the consolidation of different forms of memory.     

Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: Behavioral and electrophysiological studies

Nicotine alleviates cognitive impairment associated with a variety of health conditions. We examined the effect of chronic nicotine treatment on adult-onset hypothyroidism-induced impairment of learning and memory in rats. Hypothyroidism was induced by surgical removal of thyroid glands (thyroidectomy). One month later, chronic nicotine treatment (1 mg/kg sc, twice/day) was instituted for 4-6 weeks. Test of hippocampus-dependent spatial learning and memory in the radial arm water maze showed that hypothyroidism impaired learning as well as short-term and long-term memory retention. Chronic nicotine treatment reversed the hypothyroidism-induced learning and memory impairment. In normal rats, chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anesthetized hypothyroid rats showed severe reduction of both early-phase and late-phase long-term potentiation (LTP) magnitude, which was reversed in nicotine-treated hypothyroid rats. These results show that chronic nicotine treatment prevents hypothyroidism-induced impairment of spatial cognition and LTP.     

Selective rapid eye movement sleep deprivation impairs the maintenance of long-term potentiation in the rat hippocampus

Rapid eye movement (REM) sleep deprivation (RSD) is known to impair learning and memory. Previous studies have demonstrated that RSD induces an impairment of hippocampal long-term potentiation (LTP). In most of these studies, RSD was set up prior to LTP induction. In this work, we focused on RSD after LTP induction. We investigated the effect of RSD for 24-48 h after induction of LTP in the dentate gyrus on LTP maintenance and whether a REM rebound after 48 h RSD affected LTP. RSD rats were deprived of REM sleep by stroking their backs using a brush, whereas control rats were allowed to sleep freely. Another control group of rats was awoken during non-REM sleep (NRS) under the same conditions (NRS group). REM-deprived rats displayed a faster decay of population spike amplitudes compared with the control and NRS groups over a 24-h recording time. After 48 h RSD, there was no difference in the population spike amplitudes before or after 4 h of release from RSD. These results suggest that REM sleep after LTP induction in the dentate gyrus plays an essential role in LTP maintenance, whereas a REM rebound does not restore the RSD-induced impairment of LTP.     

Regional and time‐dependent neuroprotective effect of hypothermia following oxygen‐glucose deprivation

The neuroprotective effect of hypothermia has been demonstrated in in vivo and in vitro models of cerebral ischemia. In regard to the hippocampus, previous studies have mainly focused on CA1 pyramidal neurons, which are very vulnerable to ischemia. But the dentate gyrus (DG), in which neuronal proliferation occurs, can also be damaged by ischemia. In this study, we explored the neuroprotective effect of postischemic hypothermia in different areas of the hippocampus after mild or severe ischemia. Organotypic hippocampal slice cultures were prepared from 6‐ to 8‐day‐old rats and maintained for 12 days. Cultures were exposed to 25 or 35 min of oxygen and glucose deprivation (OGD). Neuronal damage was quantified after 6, 24, 48, and 72 h by propidium iodide fluorescence. Mild hypothermia (33°C) was induced 1 h after the end of OGD and was maintained for a period of 24 h. Short OGD produced delayed neuronal damage in the CA1 area and in the DG and to a lesser extend in the CA3 area. Damage in CA1 pyramidal cells was totally prevented by hypothermia whereas neuroprotection was limited in the DG. Thirty‐five‐minute OGD induced more rapid and more severe cell death in the three regions. In this case, hypothermia induced 1 h after OGD was unable to protect CA1 pyramidal cells whereas hypothermia induced during OGD was able to prevent cell loss. This study provides evidence that neuroprotection by hypothermia is limited to specific areas and depends on the severity of the ischemia. © 2014 Wiley Periodicals, Inc.     

The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence

Inadequate sleep is prevalent in modern societies and is known to profoundly impair cognitive function. We examined the impact of 4 weeks of regular treadmill exercise on sleep deprivation induced spatial learning and memory, synaptic plasticity and related signaling molecules in area CA1 of the rat hippocampus. Rats were exercised on a treadmill and subsequently sleep-deprived for 24h using the modified multiple platform technique. Testing of learning and short-term memory performance in the radial arm water maze showed that although sedentary sleep deprived rats were severely impaired, exercised sleep deprived rats' performance was normal. Extracellular recording from area CA1 of anesthetized rats revealed that early phase LTP (E-LTP) was markedly impaired in the sedentary sleep deprived animals, but was normal in the exercised sleep deprived group. Additionally, immunoblot analysis of CA1 area before (basal) and after expression of E-LTP indicated that the significant down-regulation of the brain derived neurotrophic factor (BDNF) and phosphorylated calcium-calmodulin dependent protein kinase II (P-CaMKII) levels in sleep deprived animals was prevented by the regular exercise regimen. The results suggest that the regular exercise protocol prevents the sleep deprivation induced impairments in short-term memory and E-LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CaMKII and BDNF associated with sleep deprivation.     

Antagonism of D1/D5 receptors prevents long‐term depression (LTD) and learning‐facilitated LTD at the perforant path–dentate gyrus synapse in freely behaving rats

Hippocampal synaptic plasticity, in the form of long‐term potentiation (LTP) and long‐term depression (LTD), enables spatial memory formation, whereby LTP and LTD are likely to contribute different elements to the resulting spatial representation. Dopamine, released from the ventral tegmental area particularly under conditions of reward, acts on the hippocampus, and may specifically influence the encoding of information into long‐term memory. The dentate gyrus (DG), as the “gateway” to the hippocampus is likely to play an important role in this process. D1/D5 dopamine receptors are importantly involved in the regulation of synaptic plasticity thresholds in the CA1 region of the hippocampus and determine the direction of change in synaptic strength that occurs during novel spatial learning. Here, we explored whether D1/D5‐receptors influence LTD that is induced in the DG following patterned afferent stimulation of the perforant path of freely behaving adult rats, or influence LTD that occurs in association with spatial learning. We found that LTD that is induced by afferent stimulation, and LTD that is facilitated by learning about novel landmark configurations, were both prevented by D1/D5‐receptor antagonism, whereas agonist activation of the D1/D5‐receptor had no effect on basal tonus or short‐term depression. Other studies have reported that in the DG, D1/D5‐receptor agonism or antagonism do not affect LTP, but agonism prevents depotentiation. These findings suggest that the dopaminergic system, acting via D1/D5‐receptors, influences information gating by the DG and modulates the direction of change in synaptic strength that underlies information storage in this hippocampal substructure. Information encoded by robust forms of LTD is especially dependent on D1/D5‐receptor activation. Thus, dopamine acting on D1/D5‐receptors is likely to support specific experience‐dependent encoding, and may influence the content of hippocampal representations of experience. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

REM sleep deprivation-induced deficits in the latency-to-peak induction and maintenance of long-term potentiation within the CA1 region of the hippocampus

Sleep loss adversely affects certain types of cognitive processing, particularly associative memory. Given that long-term potentiation (LTP) represents a putative cellular basis of learning and memory consolidation, the influence of sleep deprivation on LTP was examined. Rats were REM sleep deprived for 24, 48, or 72 h using the inverted flowerpot method in temperature-regulated chambers. Hippocampal slices taken from sleep-deprived rats were compared with home cage and pedestal control animals at 5, 15 and 60 min post-tetanization. The results indicated that at 5 min post-tetanization there were no differences in field potentials in any of the sleep-deprived or control groups, suggesting comparable levels of induction. However, analysis of latency-to-peak slope indicated that members of the 48 and 72 h sleep-deprived groups required approximately twice as long to achieve maximum slope as the 24 h group, home cage or 24, 48, 72 h pedestal controls (means 8.17, 7.50, 2.67, 4.67 and 3.17 min, respectively). At 15 min post-tetanization there were no group differences, however at 60 min post-tetanization the slopes of the field excitatory postsynaptic potentials were significantly diminished for the 24, 48 and 72 h sleep-deprived groups (means 30.44, -1.89, 1.47, respectively) as compared with home cage and pedestal controls (means 59.54, 58.42, respectively). This delay in maximal induction, and the degradation of the maintenance phase of LTP, may represent sleep deprivation-induced impairment of the underlying neurochemical mechanisms normally responsible for memory acquisition.     

Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity

Although traumatic brain injury (TBI) often results in impaired learning and memory functions, the underlying mechanisms are unknown and there are currently no treatments that can preserve such functions. We studied plasticity at CA3-CA1 synapses in hippocampal slices from rats subjected to controlled cortical impact TBI. Long-term potentiation (LTP) of synaptic transmission was markedly impaired, whereas long-term depression (LTD) was enhanced, 48 h following TBI when compared to unoperated and sham control rats. Post-TBI administration of cyclosporin A, a compound that stabilizes mitochondrial function, resulted in a highly significant amelioration of the impairment of LTP and completely prevented the enhancement of LTD. Our data suggest that alterations in hippocampal synaptic plasticity may be responsible for learning and memory deficits resulting from TBI and that agents such as cyclosporin A that stabilize mitochondrial function may be effective treatments for TBI.     

Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice

Mice carrying mutated human APPswe and PS1 (A246E) transgenes (A/P mice) show age-dependent memory impairment in hippocampus-dependent tasks. Moreover, the mice show normal learning in the water maze within a day but impairment across days. We recorded LTP in a slice preparation (CA1) and in chronically implanted animals (dentate gyrus, or DG) at 17-18 months of age. The genotypes did not differ in the basal synaptic transmission. Also, LTP induction and its maintenance over 60 min did not differ between A/P and control mice. However, the fEPSP enhancement in vivo decayed to 77% of its maximum in 24 h in A/P mice while remaining at 96% in control mice. The time course of the LTP decay in the A/P mice corresponds to their behavioral impairment and indicates that Abeta accumulation in the dentate gyrus may interfere with the signal transduction pathways responsible for memory consolidation.     

Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats

Clinical experience suggests that both hypothyroidism and stress interfere with mental concentration and memory. This electrophysiological study examined the effect of hypothyroidism and stress, separately or combined, on long-term potentiation (LTP), a widely accepted cellular model for learning and memory. Measurements of early LTP (E-LTP) were carried out in the hippocampus of urethane-anesthetized adult Wistar rats. Hypothyroidism was achieved by thyroidectomy, and the 'intruder' stress was used as a model of chronic psychosocial stress. Stimulating electrodes were placed in the left CA3 region and right angular bundle and a recording electrode was placed in the right CA1 or the dentate gyrus (DG). The results showed that in the CA1 region of the hippocampus, hypothyroid or stress partially blocked E-LTP. However, when hypothyroidism and stress were combined, they eliminated E-LTP. In contrast, no significant change in E-LTP was seen in the DG of the three groups of rats. These results suggest that impaired memory because of hypothyroidism or stress may be related to impairment of the E-LTP in the Schaffer collateral synapses but not of that of the perforant path synapses.     

Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation

Sleep fragmentation, a symptom in many clinical disorders, leads to cognitive impairments. To investigate the mechanisms by which sleep fragmentation results in memory impairments, rats were awakened once every 2 min via 30 s of slow movement on an automated treadmill. Within 1 h of this sleep interruption (SI) schedule, rats began to sleep in the 90-s periods without treadmill movement. Total non-rapid eye movement sleep (NREM) sleep time did not change over the 24 h of SI, although there was a significant decline in rapid eye movement sleep (REM) sleep and a corresponding increase in time spent awake. In the SI group, the mean duration of sleep episodes decreased and delta activity during periods of wake increased. Control rats either lived in the treadmill without movement (cage controls, CC), or had 10-min periods of movement followed by 30 min of non-movement allowing deep/continuous sleep (exercise controls, EC). EC did not differ from baseline in the total time spent in each vigilance state. Hippocampal long-term potentiation (LTP), a long-lasting change in synaptic efficacy thought to underlie declarative memory formation, was absent in rats exposed to 24 and 72 h SI. In contrast, LTP was normal in EC rats. However, long-term depression and paired-pulse facilitation were unaltered by 24 h SI. Twenty-four hour SI also impaired acquisition of spatial learning in the hippocampus-dependent water maze test. Twenty-four hour SI elevated plasma corticosterone (CORT) to levels previously shown to enhance LTP (125 ng/mL). The results suggest that sleep fragmentation negatively impacts spatial learning. Loss of N-methyl-D-aspartate (NMDA) receptor-dependent LTP in the hippocampal CA1 region may be one mechanism involved in this deficit.     

Effects of sleep disruption on rat dentate granule cell LTP in vivo

Sleep frequently fragmented or disrupted for prolonged periods can result in mood changes and impaired mental ability and performance. Sleep deprivation is defined as depriving a person or organism of sleep for various periods of fixed durations. Sleep disruption (SD) occurs when a person is awakened at any time when they would normally be sleeping; sometimes on a schedule but usually unexpectedly. It seems as if any disruption of an entrained sleep pattern can induce learning and memory impairment; and mood changes including irritability and aggression. Because memory is impaired under these conditions several studies have been conducted recently to examine changes in long term potentiation (LTP) in hippocampal brain slices following various periods of sleep deprivation in rats. Results of the present study show clearly that LTP is also decreased following SD but to a greater extent than that observed following sleep deprivation. The purpose of the present study was to measure dentate granule cell LTP in anesthetized rats following 1-, 2-, or 3-day schedules of SD using a modified flower pot procedure. Results showed that a single disruption of 3 h reduced LTP from a normal 38.7-7.6%; that endured for at least 14 h; and 9 h reduced it completely. Easy to handle animals become irritable, hyperactive, and aggressive following SD. Results are discussed in terms of stress related effects of SD and changes in synaptic plasticity.     

NMDA receptor–dependent signaling pathways that underlie amyloid β‐protein disruption of LTP in the hippocampus

Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid β‐protein (Aβ), a 40‐ to 42‐amino‐acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal‐dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C‐terminal segments or mutant variants of amyloid precursor protein, the protein from which Aβ is derived, exhibit age‐dependent spatial memory impairment and attenuated long‐term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that Aβ disturbs N‐methyl‐D ‐aspartic acid (NMDA) receptor–dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that Aβ specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca²⁺‐dependent protein phosphatase calcineurin, Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element–binding protein (CREB). The influence of Aβ on each of these downstream effectors of the NMDA receptor is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as Aβ attenuation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor currents, are briefly discussed. © 2009 Wiley‐Liss, Inc.     

Regular treadmill exercise prevents sleep deprivation-induced disruption of synaptic plasticity and associated signaling cascade in the dentate gyrus

Study objectivesEvidence suggests that regular exercise can protect against learning and memory impairment in the presence of insults such as sleep deprivation. The dentate gyrus (DG) area of the hippocampus is a key staging area for learning and memory processes and is particularly sensitive to sleep deprivation. The purpose of this study was to determine the effect of regular exercise on early-phase long-term potentiation (E-LTP) and its signaling cascade in the presence of sleep deprivation.Experimental designRats were exposed to 4 weeks of regular treadmill exercise then subsequently sleep-deprived for 24 h using the modified multiple platform model before experimentation. We tested the effects of exercise and/or sleep deprivation using electrophysiological recording in the DG to measure synaptic plasticity; and Western blot analysis to quantify the levels of key signaling proteins related to E-LTP.Measurements and resultsRegular exercise prevented the sleep deprivation-induced impairment of E-LTP in the DG area as well as the sleep deprivation-associated decrease in basal protein levels of phosphorylated and total α calcium/calmodulin-dependent protein kinase II (P/total-CaMKII) and brain-derived neurotrophic factor (BDNF). High frequency stimulation (HFS) to the DG area was used to model learning stimuli and increased the P-CaMKII and BDNF levels in normal animals: yet failed to change these levels in sleep-deprived rats. However, HFS in control and sleep-deprived rats increased the levels of the phosphatase calcineurin. In contrast, exercise increased BDNF and P-CaMKII levels in exercised/sleep-deprived rats.ConclusionsRegular exercise appears to exert a protective effect against sleep deprivation-induced spatial memory impairment by inducing hippocampal signaling cascades that positively modulate basal and stimulated levels of key effectors such as P-CaMKII and BDNF, while attenuating increases in the protein phosphatase calcineurin.     

Evaluation of the effect of pentoxifylline on sleep‐deprivation induced memory impairment

In this study, we examined the ability of Pentoxifylline (PTX) to prevent sleep deprivation induced memory impairment probably through decreasing oxidative stress. Sleep deprivation was chronically induced 8 h/day for 6 weeks in rats using modified multiple platform model. Concurrently, PTX (100 mg/kg) was administered to animals on daily basis. After 6 weeks of treatment, behavioral studies were conducted to test the spatial learning and memory using the Radial Arm Water Maze. Additionally, the hippocampus was dissected; and levels/activities of antioxidant defense biomarkers glutathione reduced (GSH), glutathione oxidized (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), were assessed. The results show that chronic sleep deprivation impaired short‐ and long‐term memories, which was prevented by chronic treatment with PTX. Additionally, PTX normalized sleep deprivation‐induced reduction in the hippocampus GSH/GSSG ratio (P < 0.05), and activities of GPx, catalase, and SOD (P < 0.05). In conclusion, chronic sleep deprivation induces memory impairment, and treatment with PTX prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus. © 2013 Wiley Periodicals, Inc.     

17β estradiol recruits GluN2B‐containing NMDARs and ERK during induction of long‐term potentiation at temporoammonic‐CA1 synapses

When circulating 17β estradiol (E2) is elevated to proestrous levels, hippocampus‐dependent learning and memory is enhanced in female rodents, nonhuman primates, and women due to heightened synaptic function at hippocampal synapses. We previously reported that proestrous‐like levels of E2 administered to young adult ovariectomized (OVX) female rats increases the magnitude of LTP at CA3 Schaffer collateral (SC)‐CA1 synapses only when dendritic spine density, the NMDAR/AMPAR ratio, and current mediated by GluN2B‐containing NMDA receptors (NMDARs) are simultaneously increased. We also reported that this increase in GluN2B‐mediated NMDAR current in area CA1 is causally related to the E2‐induced increase in novel object recognition, tying together heightened synaptic function with improved learning and memory. In addition to SC inputs, innervation from the entorhinal cortex in the temporoammonic (TA) pathway onto CA1 distal dendrites in stratum lacunosum‐moleculare is critical for spatial memory formation and retrieval. It is not known whether E2 modulates TA‐CA1 synapses similarly to SC‐CA1 synapses. Here, we report that 24 hours post‐E2 injection, dendritic spine density on CA1 pyramidal cell distal dendrites and current mediated by GluN2B‐containing NMDARs at TA‐CA1 synapses is increased, similarly to our previous findings at SC‐CA1 synapses. However, in contrast to SC‐CA1 synapses, AMPAR transmission at TA‐CA1 synapses is significantly increased, and there is no effect on the LTP magnitude. Pharmacological blockade of GluN2B‐containing NMDARs or ERK activation, which occurs downstream of synaptic but not extrasynaptic GluN2B‐containing NMDARs, attenuates the LTP magnitude only in slices from E2‐treated rats. These data show that E2 recruits a causal role for GluN2B‐containing NMDARs and ERK signaling in the induction of LTP, cellular mechanisms not required for LTP induction at TA‐CA1 synapses in vehicle‐treated OVX female rats. © 2015 Wiley Periodicals, Inc.     

Pontine-wave generator activation-dependent memory processing of avoidance learning involves the dorsal hippocampus in the rat

The aim of this study was to test the hypothesis that the dorsal hippocampus plays a critical role in pontine-wave (P-wave) generator activation-dependent memory processing of two-way active avoidance (TWAA) learning. To achieve this objective, rats were given small bilateral lesions in the CA1, dentate gyrus (DG), or CA3 region of the dorsal hippocampus by microinjecting ibotenic acid. After recovery, lesioned and sham-lesioned rats were trained on a TWAA learning paradigm, allowed a 6-hr period of undisturbed sleep, and then were tested on the same TWAA paradigm. It was found that lesions in the CA3 region impaired retention of avoidance learning. Conversely, lesions in the CA1 and DG regions had no effect on TWAA learning retention. None of the groups showed any changes in the baseline sleep-wake cycle or in the acquisition of TWAA learning. All rats showed increased rapid eye movement (REM) sleep and increased REM sleep P-wave density during the subsequent 6-hr recording period. Impaired retention in the CA3 group occurred despite an increase in REM sleep and P-wave density, suggesting that during REM sleep, the P-wave generator interacts with the CA3 region of the dorsal hippocampus to aid in consolidation of TWAA learning. The results of the present study thus demonstrate that P-wave generator activation-dependent consolidation of memory requires an intact CA3 subfield of the dorsal hippocampus. The results also provide evidence that under mnemonic pressure, the dorsal hippocampus may not be involved directly in regulating the sleep-wake cycle.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.