Functional magnetic resonance imaging in conscious animals: a new tool in behavioural neuroscience research.
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Animals↗
Biomedical subjects
J A Harder
Publications and source records attributed to J A Harder.
Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.
Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease.
The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5-HT1A agents and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.
Alzheimer Disease↗
The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys.
Central glutamate neurotransmission is modulated by an upregulatory cholinergic influence and an inhibitory serotonergic influence. In Alzheimer's disease, cognitive decline is associated with loss of both glutamatergic and cholinergic neurones (Francis et al., 1992, Progress in Neurobiology 39, 517-545). While therapeutic strategies for alleviating this cognitive decline have concentrated on restoring cholinergic tone, we suggest that 5-HT1A antagonists also have the potential to alleviate the cognitive symptoms of Alzheimer's disease. Previous studies have shown that dizocilpine (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning impairments in the common marmoset, a non-human primate. Specifically, it impairs the acquisition of shape discrimination and visuospatial conditional tasks, at doses that do not affect locomotor behaviour or coordination (Harder et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the present study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials required to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment alone, and did not differ significantly from the number of trials required under saline, demonstrating that the cognitive effects of glutamatergic blockade can be overcome by treatment with a 5-HT1A antagonist.
Animals↗
The role of the central cholinergic projections in cognition: implications of the effects of scopolamine on discrimination learning by monkeys.
In humans, administration of the cholinergic antagonist scopolamine impairs the encoding of information into long-term memory and has effects on other cognitive processes. It has been supposed that it is inhibition of the rising cholinergic projections from the basal forebrain, specifically from the basal nucleus of Meynert (NBM) to the neocortex and from the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) to the hippocampus, that results in these cognitive impairments. In this paper, we describe the effects of scopolamine treatment in monkeys on learning different sorts of visual discrimination and visuospatial conditional tasks and compare these results to the effects of lesions of the rising cholinergic projections. Experiments in rodents in which these projections have been selectively destroyed have failed to produce a consensus view of the functions of these two areas. In particular, highly specific immunotoxic lesions of the NBM have largely failed to produce changes in task performance that can be interpreted as resulting from a cognitive impairment. In monkeys, lesions of the NBM produce modest or short-lasting, impairments in visual discrimination learning, retention, and reversal, whereas lesions of the MS/VDB produce large and permanent impairments of certain types of conditional learning. Similar impairments produced by scopolamine in monkeys and additive effects of lesions of the NBM or MS/VDB with scopolamine suggest that scopolamine has these effects by acting on the rising cholinergic pathways rather than on other cholinergic systems in the brain. It is argued that the rising cholinergic projections sustain the functions of the target areas; in the case of the hippocampus in humans, the function is usually regarded as being the analysis of information in a way that is pertinent to the formation of episodic memories and in the case of the neocortex, is the analysis of information in a manner that is relevant to the cognitive processing of on-going events and the acquisition of semantic knowledge.
Acetylcholine↗
Learning impairments induced by glutamate blockade using dizocilpine (MK-801) in monkeys.
1. This study investigated the effects of dizocilpine (MK-801) on learning ability in a non-human primate. Acquisition and reversal learning of visual discrimination tasks and acquisition of visuo-spatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. Dizocilpine impaired acquisition of visuo-spatial (conditional) tasks requiring spatial responses to coloured objects, and perceptually difficult visual discrimination tasks in which stimulus objects are painted black. Dizocilpine did not, however, impair either acquisition or reversal of a simple visual discrimination task using easily discriminated, coloured objects. 2. Motor effects of dizocilpine treatment, which have been seen in other primates, were examined by observation of the marmosets in their home cages, using both an automated locomotor activity monitor and 'blind', subjective counting of the number of abnormal movements in a given time period. Locomotor activity, assessed using the automated monitor, was not significantly affected at any of the doses tested. Incoordination, assessed by human observation of abnormal movements, was significantly increased only at a dose of 30 microg kg(-1) i.m., which was twice the highest dose used to assess the effects of dizocilpine on cognition. 3. We have, therefore, found an effect of dizocilpine on acquisition and reversal of some types of cognitive task, at a dose which does not cause significant motor effects. This demonstration of a cognitive deficit associated with glutamatergic blockade in a primate may be useful in understanding the contribution of glutamatergic dysfunction to cognitive decline in neurodegenerative disease, especially Alzheimer's disease.
Animals↗
The effect of several putative cognition enhancers on a water maze acquisition deficit produced by pCPA + scopolamine combination treatment.
A combined treatment of a 3-day regimen of pCPA and low-dose scopolamine produced a significant deficit in the acquisition of a water maze task, which has been suggested as a model for the cognitive deficits of Alzheimer's disease. The putative cognition enhancers oxotremorine, captopril, ondansetron, and tacrine were used in attempts to alleviate the water maze impairment. The effects of oxotremorine were difficult to determine due to nonspecific motor effects causing alterations in swimming speed. No evidence for cognition-enhancing properties of captopril was found. Ondansetron showed a cognition-enhancing effect on one of 4 days, but only at a relatively high dose (1 mg/kg i.p.). Tacrine, however, alleviated the pCPA + scopolamine-induced cognitive deficit. This study may thus provide evidence for the usefulness of tacrine in treating spatial deficits in dementia.
Angiotensin-Converting Enzyme Inhibitors↗
Progesterone inhibits arterial smooth muscle cell proliferation.
Mortality from atherosclerotic cardiovascular disease is lower in premenopausal women than in age-matched men. It is also lower in postmenopausal women who take estrogens and progestins together rather than estrogens alone. Progesterone receptors were detected in human and rat aortic smooth muscle cells in vivo and in vitro (in subculture). We examined the effect of progesterone on proliferation of smooth muscle cells, important constituents of atherosclerotic plaques. Progesterone at physiologic levels inhibited DNA synthesis and proliferation in these cells in a dose-dependent manner, and pretreatment with the progesterone receptor antagonist RU486 blocked inhibition. Cyclin A and E messenger RNA levels decreased after progesterone treatment but those of cyclin B and D1 did not change. This cell cycle-dependent inhibition of arterial smooth muscle cell proliferation by progesterone may represent a mechanism for the hormone's protective effect against atherosclerosis.
Animals↗
Neurochemical modulation of the hippocampus in learning, remembering and forgetting in primates.
Information about the outside world is carried into the hippocampus by glutamatergic pyramidal cell pathways from the posterior association cortex via the subiculum. Processed information is carried away from the hippocampus by a reciprocal glutamatergic pathway back into posterior association cortex. These pathways are thought to be crucial for the acquisition of long term memories although it seems likely that memories are stored in cortex rather than within the hippocampus. The hippocampus is supported by functionally excitatory cholinergic modulation via fornical afferents and by functionally inhibitory serotonergic modulation specifically via 5HT1A receptors. Cholinergic modulation of the hippocampus is necessary for efficient acquisition of visuospatial tasks but not for retention of similar tasks first acquired prior to surgery. Cholinergic modulation of areas outside the hippocampus may contribute to the maintenance of memories and non-cholinergic efferents in the fornix may be required for retrieval of tasks first learnt when the hippocampus was intact. Impairments on acquisition of visuospatial tasks brought about by fornix transection can be ameliorated by direct stimulation of cholinergic receptors using pilocarpine or by blockade of the serotonergic inhibitory modulation of the hippocampus using the 5HT1A receptor antagonist, WAY100635, indicating an equal-but-opposite modulatory effect of these two neurotransmitters on hippocampal function.
Animals↗
Combined pCPA and muscarinic antagonist treatment produces a deficit in rat water maze acquisition.
A 3-day treatment with p-chlorophenylalanine (pCPA, 100 mg/kg/day) produced a significant decrease (63-89%) in 5-HT levels in both the hippocampus and the cortex of rats, while noradrenaline, adrenaline, and dopamine levels were unaffected. Treatment with pCPA alone did not affect the acquisition of a spatial learning task in the water maze. Treatment with low doses of either scopolamine (0.25 mg/kg) or atropine (10 mg/kg) was also insufficient to cause a significant impairment of water maze acquisition. However, a combined treatment of a 3-day pCPA regimen with the low dose of atropine or scopolamine produced a significant deficit in the acquisition of a water maze task.
Animals↗
Effects of lesions of different parts of the septo-hippocampal system in primates on learning and retention of information acquired before or after surgery.
Data from a large series of experiments on marmosets with lesions of the septal/diagonal band area (DB), fornix or CA1 area of the hippocampus are analysed in terms of retention of information learned before surgery, acquisition of new information and retention of information acquired after surgery. It is shown that although all three lesions impair acquisition of a specific type of new information, lesions of CA1 result in a severe retrograde amnesia but no forgetting of that type of information adequately acquired after surgery, whereas lesions of the DB do not cause retrograde amnesia but do result in significant forgetting. Monkeys with fornix transection occupied an intermediate position in their pattern of learning impairments; some animals showed evidence of forgetting, whereas the great majority showed retrograde amnesia. These data may be relevant to an understanding of the different extent of amnesia in patients with different pathology within the medial temporal lobe and associated subcortical structures.
Animals↗
The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset.
Fornix transection in the marmoset produces a specific pattern of cognitive deficits, notably a lack of ability to recall visuospatial tasks learnt preoperatively, and a deficit in acquiring new visuospatial tasks following transection. Previous work has shown that this learning impairment can be ameliorated by cholinergic agonists, suggesting that it occurs as a consequence of destroying the cholinergic projection from the vertical limb of the diagonal band to the hippocampus which runs through the fornix. We have now shown that this deficit in new learning can be significantly alleviated by the 5-HT1A antagonist, WAY 100635. This result supports the suggestion that 5-HT1A projections are inhibitory on the same target cells for which cholinergic projections are excitatory, and that loss of function in the target cells caused by loss of excitatory tone can be compensated by blockade of inhibitory tone. Since cholinergic loss in the hippocampus (and neocortex) occurs in association with cognitive decline in Alzheimer's disease, these results suggest that 5-HT1A antagonists may have a role in the treatment of some of the cognitive symptoms of dementia.
Animals↗
A pilot study to test the influence of specific prosthetic features in preventing trans-tibial amputees from walking like able-bodied subjects.
The purpose of this pilot investigation was to develop a method to test the influence of specific prosthetic features in preventing trans-tibial amputees from walking like able-bodied subjects. An able-bodied subject was fitted with a patellar-tendon-bearing orthosis incorporating several features of an amputee's prosthesis. Kinetic, kinematic and metabolic data were collected as features were systematically removed from the orthosis. While wearing the orthosis the gait of the able-bodied subject closely simulated trans-tibial amputee gait kinematically, kinetically and metabolically. Although it was obvious that the various prosthetic features influenced the kinetics and kinematics of gait, they were difficult to quantify with only a single subject. However, the two features which appeared to have the largest influence in preventing trans-tibial amputees from walking like able-bodied subjects were patellar tendon loading and a solid ankle.
Adult↗
Relation among indices of effort and oxygen uptake in below-knee amputee and able-bodied children.
The purpose of this investigation was to determine the relationships among simple methods for measuring effort in below-knee amputee (BKA) and able-bodied (AB) children. Ten BKA children and 13 AB children walked on a treadmill and selected a freely chosen walking speed (CWS). Children then walked for 2 minutes at each of three speeds: CWS, 20% above CWS, and 20% below CWS. Oxygen uptake, heart rate, physiological cost index, percent maximum heart rate, and vertical displacement of a surface marker on the sacrum were determined for each subject and speed. Linear regression with repeated measures was used to determine correlations between oxygen uptake and the four variables (p < 0.05). To evaluate the effectiveness of the regression equations, two male children not part of the AB group were tested. The proportion of explained variance arising from the significant correlations between oxygen uptake and the four measured variables were all between 0.91 and 0.92. It was concluded that the vertical displacement of a marker on the sacrum is a simple and convenient measure for a biomechanics gait laboratory to estimate effort because only standard biomechanics laboratory equipment is required. Further, in a clinical setting and/or where the necessary equipment is available heart rate, physiological cost index, and percent maximum heart rate are also adequate.
Adolescent↗
Normative ground reaction force data for able-bodied and trans-tibial amputee children during running.
The purpose of this investigation was to develop normative ground reaction force data for able-bodied (AB) and trans-tibial amputee (TTA) children during running. Two hundred AB (mean age 9.4 years, range 7-12) and 21 TTA (mean age 11.1 years, range 5-17) children ran (2.2 m/s +/- 10%) over a force platform. Ground reaction force data were normalized, averaged within groups and plotted to produce force-time curves characterizing the different leg types (i.e. able-bodied, non-prosthetic and prosthetic). In addition, discrete variables characterizing the leg type differences were determined. One way ANOVA determined significant differences between variables and a TukeyB Post Hoc analysis defined which variables were significantly different (p < 0.05). Results generally indicated differences between the three leg types with the non-prosthetic leg indicating greater forces than the prosthetic and AB legs. The results of this investigation provide normative ground reaction force data for both AB and TTA children during running and can be used for comparison with other groups of children.
Adolescent↗
Bone mineral density during puberty in western Canadian children.
To assess the influence of puberty and its associated changes in body weight and height on bone mineral density (BMD), lumbar spine (L2-L4) and femoral neck BMD were measured in 74 healthy, active children (9-16 years) using dual-photon absorptiometry. Competitive swimmers were recruited to minimize the potential effect variability in mechanical loading regime may have on bone density of the lumbar spine. Tanner staging was used to assess stage of puberty. Current dietary calcium intake was assessed by analysis of 6-day dietary records. Significant differences in spinal and femoral neck BMD occurred between early (Tanner 1 and 2) and late stages of puberty (Tanner 4 and 5), P < 0.05. A significant correlation was found between bone density and dietary calcium intake. However stepwise regression analyses demonstrated stage of puberty or body weight were the only factors which significantly affected spinal BMD, accounting for 77% and 68% of the variability respectively; while at the femoral neck, body weight accounted for 52% of the variability. These results demonstrate that when potential interacting factors are controlled for through regression analyses, differences in BMD occur mainly as a function of puberty and the associated gains in body weight.
Adolescent↗
A CAD CAM method for custom below-knee sockets.
The purpose of this investigation was to develop a numerical method for fabricating prosthetic sockets for below-knee amputees. An optical/laser digitiser scans an amputee's stump and collects three dimensional numerical data describing the surface of the limb and describing specific modification site locations. The numerical data from the laser camera representing the stump and modification sites are altered by the prosthetist using a custom computer aided design software system running on a personal computer. Using the altered numerical data a programme is created for a high resolution numerically controlled milling machine and a mould is made. The prosthetist then fabricates a socket. While the system has been tested with below-knee amputees it has been designed for application in most areas of prosthetics and orthotics. Utilising this method 15 patients were fitted. All patients subjectively stated that their "computer designed" socket fitted better than their conventionally made socket. As the research progressed and experience was gained with the system patients were normally fitted with the first socket iteration. The system overcomes five limitations existing with some of the other numerical systems: 1) accurate high resolution surface topography, 2) specific identification of subject modification sites, 3) flexible, user friendly software, 4) high resolution numerically controlled milling, and 5) integrated expansion to other prosthetic and orthotic areas.
Artificial Limbs↗
Weight distribution of below-knee amputee and able-bodied children during standing.
The purpose of this investigation was to compare weight distributions of a relatively large number of below-knee (BK) amputee and able-bodied children during two different standing positions. Twenty-one BK amputees and 200 able-bodied children volunteered as subjects for this investigation. Each child stood on a pressure plate and three sets of trial data were collected. One set of trial data was collected with both feet together on the pressure plate and two were collected with feet placed 20cm apart. The total force applied by each foot to the pressure plate was normalised by dividing by subject weight to yield foot force to body weight ratios. Data were separated into forefoot and rearfoot areas, force for the forefoot area was then calculated and normalised by dividing by total foot force to yield forefoot to whole-foot force ratios. Ratios for the two foot placement conditions and for non-prosthetic, prosthetic, dominant, and non-dominant feet were compared using paired t-tests (p < 0.05). Results indicated that: 1) BK amputee children placed more weight on their non-prosthetic limb than their prosthetic limb, yet this was not different from able-bodied children in respect of weight distribution between dominant and non-dominant limbs; 2) approximately 90% of the load on the prosthetic foot was placed on the forefoot; and 3) the load on the non-prosthetic foot was evenly distributed between the forefoot and rearfoot like that of able-bodied children. It was concluded that except for substantially more weight on the forefoot of the prosthetic leg BK amputee children stood in the same way as able-bodied children.
Adolescent↗