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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.

Action Potentials↗

Landmark learning: an illustration of associative search.

In a previous paper we defined the associative search problem and presented a system capable of solving it under certain conditions. In this paper we interpret a spatial learning problem as an associative search task and describe the behavior of an adaptive network capable of solving it. This example shows how naturally the associative search problem can arise and permits the search, association, and generalization properties of the adaptive network to be clearly illustrated.

Association Learning↗

Radial maze learning in two inbred mouse strains and their reciprocal congenics for the non-pseudoautosomal region of the Y chromosome.

The effect of the non-pseudoautosomal region of the Y chromosome on spatial learning in a radial maze task was examined in two inbred mouse strains, NZB and CBA/H, and their respective congenics for the Y(NPAR). Seven variables reflecting learning performance, learning strategy and lateralisation were measured. We found no substantial effect of the Y(NPAR) on radial maze learning, but modest influences on behavioral strategies. These findings are in agreement with previous results regarding the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields.

Animals↗

Beneficial effects of enriched environment following status epilepticus in immature rats.

BACKGROUND: There is increasing evidence that enriching the environment can improve cognitive and motor deficits following a variety of brain injuries. Whether environmental enrichment can improve cognitive impairment following status epilepticus (SE) is not known. OBJECTIVE: To determine whether the environment in which animals are raised influences cognitive function in normal rats and rats subjected to SE. METHODS: Rats (n = 100) underwent lithium-pilocarpine-induced SE at postnatal (P) day 20 and were then placed in either an enriched environment consisting of a large play area with toys, climbing objects, and music, or in standard vivarium cages for 30 days. Control rats (n = 32) were handled similarly to the SE rats but received saline injections instead of lithium-pilocarpine. Rats were then tested in the water maze, a measure of visual-spatial memory. A subset of the rats were killed during exposure to the enriched or nonenriched environment and the brains examined for dentate granule cell neurogenesis using bromodeoxyuridine (BrdU) and phosphorylated cyclic AMP response element binding protein (pCREB) immunostaining, a brain transcription factor important in long-term memory. RESULTS: Both control and SE rats exposed to the enriched environment performed significantly better than the nonenriched group in the water maze. There was a significant increase in neurogenesis and pCREB immunostaining in the dentate gyrus in both control and SE animals exposed to the enriched environment compared to the nonenriched groups. Environmental enrichment resulted in no change in SE-induced histologic damage. CONCLUSIONS: Exposure to an enriched environment in weanling rats significantly improves visual-spatial learning. Even following SE, an enriched environment enhances cognitive function. An increase in neurogenesis and activation of transcription factors may contribute to this enhanced visual-spatial memory.

Age Factors↗

Adrenoreceptor antagonist treatment influences recovery of learning following medial septal lesions and hippocampal sympathetic ingrowth.

Previous studies have demonstrated that in male rats hippocampal sympathetic ingrowth (HSI), which is induced by medial septal lesions (MS), is detrimental to recovery of spatial learning. The present study was performed in an attempt to determine if this effect was mediated through adrenergic receptor activity. Adult male Sprague-Dawley rats underwent training on a modified version (i.e., 4 arms baited) of a radial-8-arm maze task. Following attainment of learning criterion animals underwent one of three surgical procedures: CON (sham surgeries); MSGx (MS + superior cervical ganglionectomy--to prevent HSI); MS (MS + sham ganglionectomy). Reacquisition trials were performed in the same manner as initial acquisition except animals were treated with vehicle, propranolol (20 mg/kg), or phentolamine (20 mg/kg) 30 minutes prior to testing. As expected, vehicle-treated MS animals took longer to reacquire the task than MSGx animals, who were in turn more impaired than CON animals. Propranolol (beta-adrenergic antagonist) treatment impaired performance of both the MS and MSGx group, but did not alter the CON group. Phentolamine (alpha-adrenergic antagonist) increased the number of trials to reattain criterion in the CON group, had no effect in the MSGx group, and markedly improved performance in the MS group. The results suggest that HSI mediates its detrimental effects through alpha-receptors, while beta-blockade, in the setting of brain injury, is detrimental to performance regardless of the presence or absence of HSI.

Animals↗

Functional differentiation in the hippocampus.

The hippocampus is critically involved in certain kinds of memory. During memory formation, it may operate as an integrated unit, or isolated parts may be responsible for different functions. Recent evidence suggests that the hippocampus is functionally differentiated along its dorsoventral (septotemporal) axis. The cortical and subcortical connections of the dorsal and ventral hippocampus are different, with information derived from the sensory cortices entering mainly in the dorsal two-thirds or three-quarters of the dentate gyrus. Rats can acquire a spatial navigation task if small tissue blocks are spared within this region, but equally large blocks at the ventral end are not capable of supporting spatial learning. In primates, the posterior hippocampus (corresponding to the dorsal hippocampus of rodents) appears to be more important than anterior areas for encoding of spatial memory and certain forms of nonspatial memory. The ventral (or anterior) hippocampal formation is to some extent disconnected from the rest of the structure both in terms of intrahippocampal and extrahippocampal connections and may be performing functions that are qualitatively different from, and independent of, those of the dorsal hippocampal formation.

Animals↗

Mild carbon monoxide exposure and auditory function in the developing rat.

We have examined the influence of chronic mild exposure to carbon monoxide (CO) on cognitive (learning) and auditory function in the developing rat. We have demonstrated that the auditory pathway is compromised at exposures less than 50 ppm, whereas learning was not influenced at 100 ppm. Artificially reared rat pups were exposed to CO during the brain growth spurt and onset of myelination. Spatial learning was assessed using the Morris Water Maze and three tests of auditory function: (1) auditory brainstem conduction times; (2) the amplitude of the eighth nerve's action potential; and (3) otoacoustic emissions carried out on rat pups (age 22- 24 days). The pups were gastrostomy-reared on a rat milk substitute and chronically exposed to CO at discrete concentrations in the range of 12-100 ppm from 6 days of age to post-weaning at 21-23 days of age. We found no difference in auditory brainstem conduction times at all CO concentrations in comparison to non-exposed controls. There was a difference in otoacoustic emissions for test and controls at CO concentrations of 50 ppm but not at lower concentrations. There was a consistent attenuation of the amplitude of the eighth nerve's action potential, even at the lowest CO exposure examined. The attenuation of the amplitude of the action potential of the eighth nerve at 50 ppm carbon monoxide exposure did not completely recover by 73 days of age. We conclude that prolonged mild exposure to carbon monoxide during development causes measurable functional changes at the level of the eighth cranial nerve.

Acoustic Stimulation↗

The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats.

The highly potent and selective 5-HT(6) receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.

Administration, Oral↗

Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: opportunities for novel drug development in aging.

Superoxide dismutase (SOD) is one of the most effective mechanisms in physiology for inactivating reactive oxygen species. Elevated SOD activity can be therapeutically useful by protecting against oxidative stress-induced neurotoxicity. Acutely increased extracellular-SOD (EC-SOD) activity protects against neurobehavioral impairment caused by acute ischemia. Chronically increased EC-SOD activity may also be therapeutically useful by protecting against chronic oxidative stress-induced neurobehavioral damage that accumulates during the aging process. We have found that mice with genetic overexpression of EC-SOD do not show the aging-induced decline in learning and memory that control, wild type mice show. From 14-22 months of age, the EC-SOD overexpressing mice have significantly better spatial learning working memory function than that of controls. This effect is specific to the aging period. Young adult EC-SOD overexpressing mice do not have better learning and memory function than controls. The beneficial effects of increased EC-SOD activity with aging may be achieved without risk of impairment during younger ages by chronically administering EC-SOD mimetics from mature adulthood into the aging period. Novel EC-SOD mimetics may be useful in attenuating aging-induced cognitive impairments and other aspects of physiological decline with aging.

Aging↗

Orexin-saporin lesions of the medial septum impair spatial memory.

The medial septum and diagonal band of Broca (MSDB) provide a major input to the hippocampus and are important for spatial learning and memory. Although electrolytic MSDB lesions have prominent memory impairing effects, selective lesions of either cholinergic or GABAergic MSDB neurons do not or only mildly impair spatial memory. MSDB neurons are targets of orexin-containing neurons from the hypothalamus. At present, the functional significance of orexin afferents to MSDB is unclear, and the present study investigated a possible involvement of orexin innervation of the MSDB in spatial memory. Orexin-saporin, a toxin that damages neurons containing the hypocretin-2 receptor, was administered into the MSDB of rats. Rats were subsequently tested on a water maze to assess spatial reference memory and a plus maze to assess spatial working memory. At 100 ng/microl, orexin-saporin destroyed primarily GABAergic septohippocampal neurons, sparing the majority of cholinergic neurons. At 200 ng/microl, orexin-saporin almost totally eliminated GABAergic septohippocampal neurons and destroyed many cholinergic neurons. Spatial reference memory was impaired at both concentrations of orexin-saporin with a dramatic impairment observed for 24-h retention. Short-term reference memory was also impaired at both concentrations. Rats treated with 200 ng/microl, but not 100 ng/microl, of orexin-saporin were also impaired on a spontaneous alternation task, showing a deficit in spatial working memory. Our results, together with previous studies, suggest that orexin innervation of the MSDB may modulate spatial memory by acting on both GABAergic and cholinergic septohippocampal neurons.

Animals↗

Serial lesion effect in rat medial frontal cortex as a function of age.

This experiment examined the potential for behavioral recovery in juvenile, adult, and senescent rats following serial lesions of medial frontal cortex. The subjects were trained on spatial delayed alternation in a T-maze under conditions designed to enhance the probability of a serial lesion effect. All subjects were given extensive handling and adaptation to the maze, interoperative training, and long interoperative and postoperative intervals. There were several major behavioral findings: (a) the aged intact subjects were not impaired in their ability to learn spatial delayed alternation, (b) one-stage bilateral lesions of frontal cortex produced equivalent deficits on spatial delayed alternation at all ages, (c) subjects in all of the age categories demonstrated a serial lesion effect, but (d) the 150 day and 570 day serial lesions groups demonstrated significantly better performances than the 35 day serial lesions group on several measures of performance.

Aging↗

Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.

It is widely believed that the brain processes information and stores memories by modifying and stabilizing synaptic connections between neurons. In experimental models of synaptic plasticity, such as long-term potentiation (LTP), the stabilization of changes in synaptic strength requires rapid de novo RNA and protein synthesis. Candidate genes, which could underlie activity-dependent plasticity, have been identified on the basis of their rapid induction in brain neurons. Immediate-early genes (IEGs) are induced in hippocampal neurons by high-frequency electrical stimulation that induces LTP and by behavioral training that results in long-term memory (LTM) formation. Here, we investigated the role of the IEG Arc (also termed Arg3.1) in hippocampal plasticity. Arc protein is known to be enriched in dendrites of hippocampal neurons where it associates with cytoskeletal proteins (Lyford et al., 1995). Arc is also notable in that its mRNA and protein accumulate in dendrites at sites of recent synaptic activity (Steward et al., 1998). We used intrahippocampal infusions of antisense oligodeoxynucleotides to inhibit Arc protein expression and examined the effect of this treatment on both LTP and spatial learning. Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity.

Animals↗

Morris water task impairment and hypoactivity following cysteamine-induced reductions of somatostatin-like immunoreactivity.

The effects of cysteamine-induced reductions of somatostatin-like immunoreactivity (SLI) on spatial learning, passive avoidance, and locomotor activity were examined in adult Sprague-Dawley rats. Cysteamine hydrochloride (100 mg/kg, s.c.) produced 54% and 50% reductions in SLI in cortex and hippocampus, respectively, and impaired escape latencies and spatial probe behavior in the Morris water task. Although cysteamine-treated rats displayed hypoactivity in the activity boxes, their swim speed in the Morris water task was unaffected. Cysteamine did not impair passive avoidance retention when administered immediately following training or prior to daily retention testing. These results suggest a role for somatostatin in spatially-mediated behaviors in rats.

Animals↗

Learning deficits after unilateral AF64A lesions in the rat basal forebrain: role of cholinergic and noncholinergic systems.

Rats were given unilateral infusions of ethylcholine aziridinium ion (AF64A) into the basal forebrain (BF). BF-lesioned rats had significant acquisition and retention deficits in two different types of learning tasks (water maze and active avoidance). Choline acetyltransferase activity was lower than control in the frontal cortex but not in the hippocampus or striatum. AF64A markedly reduced the levels of norepinephrine, dopamine, and serotonin in all brain regions studied. However, L-glutamic acid decarboxylase activity was not altered by AF64A injection. Cholinergic agents (physostigmine and arecoline) ameliorated the AF64A-induced learning deficits in the water maze task but not in the active avoidance task. Noncholinergic agents (desipramine and L-dopa) ameliorated the AF64A-induced avoidance deficits in the active avoidance task but not in the water maze task. 5-Methoxy-N,N-dimethyltryptamine did not improve either active avoidance or water maze learning. These results suggest that intra-BF injection of AF64A produces extensive brain dysfunction and that different neuronal systems are involved in associative and spatial learning.

Animals↗

Effects of methanol extract of Uncariae Ramulus et Uncus on ibotenic acid-induced amnesia in the rat.

In the present study, we investigated the effects of Uncariae Ramulus et Uncus (UR) on learning and memory in the Morris water maze task and the central cholinergic system of rats with excitotoxic medial septum (MS) lesion. In the water maze test, the animals were trained to find a platform in a fixed position during 6 days and then received a 60-s probe trial in which the platform was removed from the pool on the 7th day. Ibotenic lesion of the MS showed impaired performance of the maze test and severe cell losses in the septohippocampal cholinergic system (SHC), as indicated by decreased choline acetyltransferase-immunoreactivity and acetylcholinesterase-reactivity in the hippocampus. Daily administrations of UR (100 mg/kg, i.p.) for 21 consecutive days produced significant reversals of ibotenic acid-induced deficit in learning and memory. These treatments also reduced the loss of cholinergic immunoreactivity in the hippocampus induced by ibotenic acid. These results demonstrated that impairments of spatial learning and memory may be attributable to degeneration of SHC neurons and that UR ameliorated learning and memory deficits partly through neuroprotective effects on the central acetylcholine system. Our studies suggest that UR may be useful in the treatment of Alzheimer's disease.

Acetylcholinesterase↗

[Effect of lead on learn and memory and release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons].

OBJECTIVE: To study effect of lead on learn and memory and the release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons. METHODS: Using a water maze we measured the ability of spatial learning of mouses. Digesting with low concentration of trypsin and gently triturating mode were used to dissociate hippocampal neurons. Using inositol 1,4,5-triphosphate (IP3) sensitive calcium store antagonist-heparine and non-IP3 sensitive calcium store (ryanodine) antagonist-procaine to stimulate hippocampal neurons, and observed the effect of Pb2+ on [Ca2+]i of hippocampal neurons by Fura-2 double wavelength fluoremetry. RESULTS: In the Morris water maze task, results indicated that mouses having drink lead water displayed significant impairment in their performance, and this extent of impairment showed in lead concentration dependent manner. Compared with control group, in condition of none of extracellular free calcium, 25 micromol x L(-1) of Pb2+ induced markedly increase of intracellular free calcium of hippocampal neurons in mouse. Heparin (IP3 sensitive calcium store antagonist) of 30 microg x ml(-1) and procaine (non-IP3 sensitive calcium store atagonist) of 0.1 mg x ml(-1) blocked the increases of [Ca2+]i in mouse hippocampal neurons elicited by 25 micromol x L(-1) of Pb2+. CONCLUSION: Chronic exposure to lead (Pb2+) reduces the ability of spatial learing and memory of mice. High level of Pb2+ facilitated release of intracellular free calcium from IP3 sensitive and non-IP3 sensitive calcium store and induced the increases of intracellular free calcium in mouse hippocampal neurons.

Animals↗

Overexpression of calbindin D(28k) in dentate gyrus granule cells alters mossy fiber presynaptic function and impairs hippocampal-dependent memory.

Calcium is a key signaling ion for induction of synaptic plasticity processes that are believed to influence cognition. Mechanisms regulating activity-induced increases in neuronal calcium and related synaptic modifications are not fully understood. Moreover, involvement of specific synapses in discrete aspects of spatial learning remains to be elucidated. We used herpes simplex amplicons to overexpress calbindin D(28k) (CaBP) selectively in dentate gyrus (DG) granule cells. We then examined the effects on hippocampal network activity by recording evoked synaptic responses in vivo and in vitro and analyzing hippocampal-dependent behavior. Relative to Lac-Z- and sham-infected controls, CaBP overexpression increased mossy fiber (MF-CA3) excitatory postsynaptic potentials and reduced paired-pulse facilitation (PPF), suggesting an increase in presynaptic strength. Additionally, CaBP overexpression reduced long-term potentiation (LTP), caused a frequency-dependent inhibition of post-tetanic potentiation (PTP), and impaired spatial navigation. Thus, increasing CaBP levels selectively in the DG disrupts MF-CA3 presynaptic function and impairs spatial cognition. The results demonstrate the power of gene delivery in the study of the neural substrates of learning and memory and suggest that mossy fiber synaptic plasticity is critical for long-term spatial memory.

Animals↗

Age-related decline in water maze learning and memory in rats: strain differences.

Rats display an age-related impairment in learning and memory; however, few studies have systematically examined this relationship in multiple strains. The present study used a repeated acquisition water maze task to test the hypothesis that age-related decreases in learning and memory occur at different rates in three strains of rats, i.e. Sprague-Dawley (SD), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. All three strains of rats displayed age-related decreases in spatial learning and memory; however, the rate of decline differed between the strains. Compared to young rats of the same strain, only SHR were significantly impaired at 12 months of age. All three strains displayed moderate impairment in learning the task at 18 months of age, and at 24 months of age all three strains of rats were severely impaired in the task, but SD performed best at 18 and 24 months of age. Further, SD and SHR displayed a probe trial bias at 3 months of age, but only SD had a bias at 12 months of age and none of the rats showed the bias at later ages. Thus, in these three strains, age-related impairment of spatial memory proceeds at different rates.

Aging↗