[What made the elderly lady feel dizzy?].
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Aged↗
Biomedical subjects
H Tanila
Publications and source records attributed to H Tanila.
Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta- mice.
Hippocampal "place cells" fire selectively when an animal is in a specific location. The fine-tuning and stability of place cell firing was compared in two types of mutant mice with different long-term potentiation (LTP) and place learning impairments. Place cells from both mutants showed decreased spatial selectivity. Place cell stability was also deficient in both mutants and, consistent with the severities in their LTP and spatial learning deficits, was more affected in mice with a point mutation [threonine (T) at position 286 mutated to alanine (A)] in the alpha calmodulin kinase II (alphaCaMKIIT286A) than in mice deficient for the alpha and Delta isoforms of adenosine 3'5'-monophosphate-responsive element binding proteins (CREBalphaDelta-). Thus, LTP appears to be important for the fine tuning and stabilization of place cells, and these place cell properties may be necessary for spatial learning.
Animals↗
Unique features in the processing of spatial information by the aged hippocampus as shown by place cell recording studies: a response to Peter Rapp's commentary "Representational organization in the aged hippocampus".
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Aging↗
Cognitive changes in mice following moderate MPTP exposure.
We evaluated the cognitive effects of two moderate doses (30 mg/kg x 3 every 12 h and 20 mg/kg x 6 every 8 h, i.p.) of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in mice. The dose of 30 mg/kg x 3 caused about 60% depletion of striatal dopamine but did not reduce the levels of its metabolites. Mice treated with MPTP did not differ from controls in their motor behavior in the open field. Mice treated with MPTP were comparable to controls in T-maze delayed alternation with fixed delays but were impaired when trials with mixed 20 s and 120 s delays were presented, indicative of a spatial working memory impairment. Dexmedetomidine at 10 microg/kg (s.c.) slightly improved delayed alternation performance in all groups but also slowed initiation of the motor response. Mice treated with MPTP at the dose of 30 mg/kg x 3 were less sensitive to this adverse effect of dexmedetomidine. The impairment in spatial working memory after MPTP exposure in mice parallels the findings in monkeys, but the deficit is much less severe.
3,4-Dihydroxyphenylacetic Acid↗
Brain aging: changes in the nature of information coding by the hippocampus.
Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information.
Aging↗
Brain aging: impaired coding of novel environmental cues.
Studies of the spatial memory capacities of aged animals usually focus on performance during the learning of new environments. By contrast, efforts to characterize age-related alterations in spatial firing information processing by hippocampal neurons typically use an environment that is highly familiar to the animals. In the present study we compared the firing properties of hippocampal neurons in young adult and aged rats as they acquired spatial information about new environmental cues. Hippocampal complex spike cells were recorded while rats performed a radial arm maze task in a familiar environment and then recorded again after many of the spatial cues were changed. After the change in the environment, in aged rats 35-42% of place fields retained their original shape and location with respect to the maze center, although they usually rotated to another arm. By contrast, all place fields in young animals either disappeared or appeared in a new location. Some of the new place fields appeared in the new environment during the first 5 min of exploration, whereas others needed more than 30 min to develop fully. In the familiar environment spatial selectivity of place cells was similar in young and aged rats. By contrast, when rats were placed into a new environment, spatial selectivity decreased considerably in aged memory-impaired rats compared with that of young rats and aged rats with intact memory performance.
Aging↗
Discordance of spatial representation in ensembles of hippocampal place cells.
The extent to which small ensembles of neighboring hippocampal neurons alter their spatial firing patterns concurrently in response to stimulus manipulations was examined in young adult rats as well as in aged rats with and without memory impairment. Recordings from CA1 and CA3 cells were taken as rats performed a spatial radial-maze task that employed prominent distal visual stimuli attached to dark curtains surrounding the maze and local cues on each maze arm provided by inserts with distinctive visual, tactile, and olfactory stimuli. To test the influence of the different stimulus subsets, the distal and local cues were rotated 90 degrees in opposite directions (a Double Rotation). In response to this manipulation, place fields could maintain a fixed position to room coordinates, rotate with either the local or the distal cues, disappear, or new fields could appear. On average 79% of the cells within an ensemble responded in the same way, but only 37% of all ensembles were fully concordant. Typically discordant ensembles had place fields that rotated with one set of cues, whereas the other fields disappeared or new fields appeared. Ensembles in which the place fields rotated in two opposite directions were less frequent in young rats than would be expected by the occurrence of the individual responses, indicating selective competition between directly conflicting representations and ultimate suppression of one. These findings indicate that hippocampal neurons independently encode distinct subsets of the cues in a complex environment, although processing within the hippocampal network may actively reduce the simultaneous representation of conflicting orientation information. This kind of population activity might reflect the higher-order organization of new memories within an established knowledge framework or schema. Concordance was higher in aged memory-impaired rats than in young rats, and the suppression of conflicting representations was absent in these rats. These findings suggest that age-related memory impairment is at least in part associated with a decrease in the scope of information coded and in the coordination of encoded representations.
Animals↗
Cues that hippocampal place cells encode: dynamic and hierarchical representation of local and distal stimuli.
Hippocampal place fields were recorded as rats explored a four-arm radial maze surrounded by curtains holding distal stimuli and with distinct local tactile, olfactory, and visual cues covering each arm. Systematic manipulations of the individual cues and their interrelationships showed that different hippocampal neurons encoded individual local and distal cues, relationships among cues within a stimulus set, and the relationship between the local and distal cues. Double rotation trials, which maintained stimulus relationships within distal and local cue sets, but altered the relationship between them, often changed the responses of the sampled neural population and produced new representations. After repeated double rotation trials, the incidence of new representations increased, and the likelihood of a simple rotation with one of the cue sets diminished. Cue scrambling trials, which altered the topological relationship within the local or distal stimulus set, showed that the cells that followed one set of controlled stimuli responded as often to a single cue as to the constellation. These cells followed the single cue when the stimulus constellation was scrambled, but often continued firing in the same place when the stimulus was removed or switched to respond to other cues. When the maze was surrounded by a new stimulus configuration, all of the cells either developed new place fields or stopped firing, showing that the controlled stimuli had persistent and profound influence over hippocampal neurons. Together, the results show that hippocampal neurons encode a hierarchical representation of environmental information.
Animals↗
Dissociation of mnemonic coding and other functional neuronal processing in the monkey prefrontal cortex.
Single-neuron activity was recorded in the prefrontal cortex of three monkeys during the performance of a spatial delayed alternation (DA) task and during the presentation of a variety of visual, auditory, and somatosensory stimuli. The aim was to study the relationship between mnemonic neuronal processing and other functional neuronal responsiveness at the single-neuron level in the prefrontal cortex. Recordings were performed in both experimental situations from 152 neurons. The majority of the neurons (92%) was recorded in the prefrontal cortex. Nine of the neurons were recorded in the dorsal bank of the anterior cingulate sulcus and two in the premotor cortex. Of the total number of neurons recorded in the prefrontal area, 32% fired in relation to the DA task performance and 39% were responsive to sensory stimulation or to the movements of the monkey outside of the memory task context. Altogether 42% of the recorded neurons were neither activated by the various stimuli nor by the DA task performance. Three types of task-related neuronal activity were recorded: delay related, delay and movement related, and movement related. The majority of the task-related neurons (n = 33, 73%) fired in relation to the delay period. Of the delay-related neurons, 26 (79%) were spatially selective. The number of spatially selective delay-related neurons of the whole population of recorded neurons was 18%. Twelve task-related neurons (27%) fired in relation to the response period of the DA task. Five of these neurons changed their firing rate during the delay period and were classified as delay/movement-related neurons. Contrary to the delay-related neurons, less than half (42%) of the response-related neurons were spatially selective. The majority (70%) of the delay-related neurons could not be activated by any of the sensory stimuli used and did not fire in relation to the movements of the monkey. The remaining portion of the delay-related neurons was activated by stationary and moving visual stimuli or by visual fixation of an object. In contrast to the delay-related neurons, the majority (66%) of the task-related neurons firing in relation to the movement period were also responsive to sensory stimulation outside of the task context. The majority of these neurons responded to visual stimulation, visual fixation of an object, or tracking eye movements. One neuron gave a somatomotor and another a polysensory response. The majority (n = 37, 67%) of all neurons responding to stimulation outside of the task context did not fire in relation to the DA task performance. The majority of their responses was elicited by visual stimuli or was related to visual fixation of an object or to eye movements. Only six neurons fired in relation to auditory, somatosensory, or somatomotor stimulation. This study provides further evidence about the significance of the dorsolateral prefrontal cortex in spatial working memory processing. Although a considerable number of all DA task-related neurons responded to visual, somatosensory, and auditory stimulation or to the movements of the monkey, most delay-related neurons engaged in the spatial DA task did not respond to extrinsic sensory stimulation. These results indicate that most prefrontal neurons firing selectively during the delay phase of the DA task are highly specialized and process only task-related information.
Animals↗
The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats.
A selective alpha-2 agonist medetomidine, a selective alpha-2 antagonist atipamezole and lidocaine were injected into the prefrontal cortex of aged rats that had been trained to perform a delayed alternation (DA) task in a T maze. Medetomidine at the dose of 0.01 microgram/microliter improved the memory task performance in four of five rats. The fifth rat improved its performance at the dose of 1.0 microgram/microliter. Atipamezole did not have any effect on the task performance. The effect of a systemic dose of medetomidine (3 micrograms/kg), which was previously shown to improve the task performance in old rats, was reversed by an intracortical injection of atipamezole. Lidocaine impaired the DA performance significantly. The results suggest that the beneficial effects of medetomidine on the working memory of old rats are mediated at least partly through the prefrontal cortex.
Adrenergic alpha-Agonists↗
Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys.
The effects of a highly selective alpha-2 adrenergic agonist medetomidine and its antagonist atipamezole were studied on the delayed response task performance of aged monkeys. Medetomidine, at the dose of 1.0 micrograms/kg, improved the memory task performance, whereas atipamezole had no effect on the performance at any dose. It has earlier been shown that alpha-2 adrenergic agonists clonidine and guanfacine improve age-associated memory impairment, but also contradictory effects of clonidine have been reported. There is evidence that the ability of alpha-2 agonists to improve DR task performance is due to its selective action on the alpha-2A receptor subtype. Clonidine and medetomidine are much less selective than guanfacine with respect to alpha-2A and alpha-2B receptor subtypes. Therefore, we also studied the effect of guanfacine on the memory task performance of the same aged monkeys in the same testing conditions to compare the effectiveness of these two alpha-2 adrenergic compounds. Guanfacine improved memory task performance at the dose of 0.0001 mg/kg. The results indicate that alpha-2 agonists, independent of their different selectivity with respect to alpha-2A/2B receptor subtypes, are beneficial drugs in improving the performance in the delayed response task.
Adrenergic alpha-Agonists↗
[Memory dysfunction of a patient, after temporal lobectomy].
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Adult↗
Activation of alpha 2-adrenergic receptors decreases nerve trauma-induced afferent barrage but not autotomy.
Effects of the selective alpha 2-adrenoceptor agonist, medetomidine, on a compound volley of a tibial nerve stimulation-evoked spinal reflex, pain-induced phrenic motor responses and on postoperative neuropathic pain behavior were studied in rats. Medetomidine (0.3 mg/kg) decreased the amplitude of the compound volley recorded from peroneal nerve in response to tibial stimulation in pentobarbital (40 mg/kg) anesthetized rats. Atipamezole, an alpha 2-adrenoceptor antagonist (1.5 mg/kg) fully restored the response when given 60 min after the medetomidine administration. Pain-evoked phrenic motor responses were completely inhibited upon combination anesthesia by pentobarbital (40 mg/kg) and medetomidine (0.3 mg/kg) (PB+M) but not upon plain pentobarbital anesthesia (50 or 60 mg/kg) (PB50,PB60). To study the effect of medetomidine on postoperative neuropathic pain behavior (autotomy), transection of sciatic nerve was done under PB+M, PB50 or PB60 anesthesia. No differences between the groups were found in the postoperative pain behavior during eight-week follow up. The results show that activation of alpha 2-adrenergic receptors by medetomidine under pentobarbital anesthesia mitigates trauma-induced afferent barrage, whereas it does not reduce the subsequent autotomy.
Adrenergic alpha-2 Receptor Agonists↗
Regional distribution of functions in dorsolateral prefrontal cortex of the the monkey.
Single-cell responses were obtained from 352 neurons in dorsolateral prefrontal cortex (Walker's areas 9 and 46) of three monkeys. The neurons were classified functionally according to their responsiveness to visual, auditory and somatosensory stimulation, and to correlation of their activity with spontaneous eye or limb movements. A comparison between the distribution of different functions and known modality-specific anatomical connections to various sectors of this area showed a good correspondence. On average somatosensory and motor neurons were located more ventrally than the remaining ones, and were concentrated to the middle third of the inferior bank of principal sulcus and adjacent inferior convexity, where a number of somatosensory projections overlap. Oculomotor neurons were found caudally in both banks of principal sulcus and in a narrow band on the dorsal convexity, coinciding with the projection fields of areas 7a and 7ip of posterior parietal cortex, superior colliculus, and paramedian pontine tegmentum. Other functions were scatteredly distributed. Visual neurons which preferred moving to stationary stimuli were located more caudally and dorsally than other visual neurons. The present study shows that a parcellation of dorsolateral prefrontal cortex proposed on the basis of anatomical connectivity is also functionally evident.
Animals↗
Inhibition of intestinal motility and reversal of postlaparotomy ileus by selective alpha 2-adrenergic drugs in the rat.
BACKGROUND: The effects of selective alpha-agonist medetomidine and alpha 2-antagonist atipamezole on gastrointestinal motility were studied. METHODS: The passage of intragastrically administered Evans blue in the small bowel of unanesthetized rats was followed, and the stomachs were weighted after killing the rats. RESULTS: Subcutaneous medetomidine, 0.01-0.1 mg/kg, was found to delay small intestinal transit but not gastric emptying, with a maximal effect seen at 0.03 mg/kg. Atipamezole fully reversed the effect of 0.1 mg/kg of medetomidine with a dose of 2.5 mg/kg. Atipamezole alone did not affect small intestinal transit. Subcutaneous morphine, 6 mg/kg, delayed gastric emptying and small intestinal transit, whereas intraperitoneal morphine only delayed gastric emptying. Subcutaneous atipamezole, 0.06 mg/kg, was partially able to reverse the delayed intestinal transit but did not inhibit morphine-induced gastric retention. Subcutaneous atipamezole, 0.06 mg/kg, reversed laparotomy-induced ileus completely. CONCLUSIONS: Atipamezole may provide a useful treatment for postlaparotomy ileus.
Adrenergic alpha-Agonists↗
Effects of medetomidine, a selective alpha 2-agonist, on position discrimination and reversal learning in aged rats.
The effect of a low dose (3 micrograms/kg) of medetomidine on cognitive performance of aged rats was examined in position discrimination and reversal learning in a T-maze. In Experiment 1, the reversal was introduced after 3 days of position habit acquisition and in Experiment 2 in the same session. Open-field and novelty-suppressed feeding tests were undertaken before drug testing to relate the cognitive effect of medetomidine with exploratory activity and neophobia of individual rats. Medetomidine slightly impaired the acquisition of position discrimination in both sexes and decreased perseveration in the reversal of a well-established position habit in females. The correlation of these findings with exploratory activity and neophobia is discussed.
Adrenergic alpha-Agonists↗
Functional properties of dorsolateral prefrontal cortical neurons in awake monkey.
Electrophysiological single-cell responses were studied in 134 neurons in Walker's areas 46 and 9 of the prefrontal cortex of two stumptail macaques. The neurons were systematically tested for various visual, auditory and somatosensory stimuli. In addition, the rate of neuronal discharges were observed in relation to provoked or spontaneous eye or limb movements. More than half (52.2%) of the neurons responded to stimulation, and the majority of them gave visual responses. Eighty percent of the visual neurons responded to the presentation of various objects, the remaining being selective for meaningful objects or the appearance and movements of the experimenter. Auditory, somatosensory, somatomotor and oculomotor responses were also encountered; 9.0% of the recorded neurons were multimodal. Despite the large stimulus repertoire 47.8% of the neurons were found to be only spontaneously active.
Animals↗
Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats.
The effects of a novel, highly selective alpha-2 agonist, medetomidine, and its antagonist, atipamezole, were studied on the working memory of rats performing a spatial delayed alternation task. Testing was performed in two stages, at the age of 8.3 months (mean) and again when the rats were 17.6 months (mean). A low dose (3 micrograms/kg) and a high dose (30 micrograms/kg) of medetomidine improved the performance of the old rats in the memory task but had no effect on the young rats. The dose-response curve of medetomidine resembles that of guanfacine, another alpha-2 agonist. At the low dose of medetomidine (3 micrograms/kg) the animals showed no signs of sedation. Since medetomidine even at a low dose has a beneficial effect on the memory performance of old rats, it could be a good candidate for the treatment of age-associated memory dysfunction.
Adrenergic alpha-Agonists↗