Complex maze learning in rodents as a model of age-related memory impairment

Research is reviewed concerning the age-related learning deficit observed in a 14-unit T-maze (Stone maze). Rats and mice of several strains representing different adult age groups are first trained to criterion in one-way active avoidance in a straight runway. Then training in the Stone maze is conducted which involves negotiation of five maze segments to avoid footshock. Results indicate a robust age-related impairment in acquisition observed in males and females, and in outbred, inbred, and hybrid strains. Pharmacological studies using the muscarinic antagonist, scopolamine, in young and aged rats indicate cholinergic involvement for accurate encoding during acquisition of this task. Retention aspects of storage and retrieval do not appear to be affected by scopolamine treatment. Bilateral electrolytic lesions to the fimbria-fornix of young rats also produce an acquisition deficit to implicate involvement of the septo-hippocampal cholinergic system in Stone maze learning. A salient feature of Stone maze performance is the tendency to demonstrate an alternation strategy in solving the maze. This strategy is exacerbated by impairment of cholinergic neurotransmission with either scopolamine treatment or fimbria-fornix lesions. Various models of hippocampal function are applied toward the psychological characterization of the Stone maze task without complete success. Future research is outlined to provide more thorough psychological characterization of maze performance, to analyze the specificity of cholinergic involvement in the task, and to test possible therapeutic interventions for alleviating the age-related impairments observed.     

In vitro associative conditioning of Hermissenda: cumulative depolarization of type B photoreceptors and short-term associative behavioral changes

Cumulative depolarization of Hermissenda type B photoreceptors, a short-term neural correlate of associative learning, was produced by simulating associative training in the isolated nervous system (in vitro conditioning). This simulation entailed stimulation and recording from three classes of neurons normally affected by the associative training procedure: a type B photoreceptor, the silent/excitatory (S/E) optic ganglion cell, and a statocyst caudal hair cell. Exposure of the isolated nervous system to five simultaneous pairings of light and current-induced impulse activity of the caudal hair cell resulted in an average 10-mV depolarization of type B cells. Cumulative depolarization was found to be pairing specific, to occur with a minimal number of training trials, and was paralleled by short-term pairing-specific changes in phototactic behavior for the intact animal. Two important determinants of cumulative depolarization were found to be the magnitude and duration of the long-lasting depolarization (LLD) response of type B cells to light, and a pairing-specific synaptic facilitation of the LLD response. The synaptic facilitation arose from two distinct sources: increased excitatory postsynaptic potential (EPSP) feedback on B cells following light and caudal hair cell stimulation pairings, and disinhibition of the type B photoreceptor following pairings. The S/E optic ganglion cell was found to be a potent regulator of B cell EPSPs. Cumulative depolarization was substantially reduced when the S/E cell was hyperpolarized throughout the course of pairings. Conversely, pairings of light with depolarizing current stimulation of the S/E cell were sufficient to produce cumulative depolarization of B cells. Precluding disinhibition of the B cell from the caudal hair cell was also found to attenuate cumulative depolarization. Additional constraints, inherent to the neural organization of the visual and statocyst neural systems were found to further limit the degree of cumulative depolarization. Among the most important of these were the interpairing interval and light intensity. Exposure of intact animals of five pairings of light and rotation resulted in short-term suppression of phototactic behavior. Like the cumulative depolarization of B cells with in vitro conditioning procedures, these changes were relatively pairing specific and persisted for comparable durations of time. Cumulative depolarization of B cells appears to be an important initial step in the production of long-term associative neural and behavioral changes in Hermissenda.     

Classical conditioning: the Rosetta stone for brain substrates of age-related deficits in learning and memory

The three chapters on the use of classical conditioning paradigms to investigate neurobiological and behavioral substrates of memory impairments with aging are in close agreement on all key issues. Based on these chapters, it is argued here that classical conditioning of discrete behavioral responses in rabbit and other mammals is among the most promising animal models of the human condition in which to analyze brain mechanisms of normally occurring age-related deficits in learning and memory.     

Orbital decompression in endocrine orbitopathy: advantages and disadvantages of different methods

Based on the disease activity score, current indications for orbital decompression are described. After that, all contemporary decompression techniques are mentioned and their advantages and disadvantages are described. Transpalpebral fat resection is also included. Results (reduction of proptosis, complications) are presented for the coronal and transconjunctival (swinging eyelid and transcaruncular orbitotomy) approach used by the author and discussed in comparison with other methods.     

Dissociation of associative and nonassociative concomitants of classical fear conditioning in the freely behaving rat

An acoustic stimulus previously paired with footshock elicits stereotyped increases in arterial pressure and heart rate and induces freezing behavior in freely behaving rats. Although the arterial pressure and freezing responses differ between groups given paired and random presentations of the tone and shock, the increases in heart rate do not. These observations, if taken at face value, suggest that the arterial pressure and freezing responses reflect associative learning but that the heart rate change is a nonassociative or a pseudoconditioned response. In this article we describe three experiments aimed at determining why the CS elicits similar increases in heart rate in groups given paired and random training. The first study demonstrates that regardless of the pseudoconditioning control procedure used (random, backwards, shock-alone, or naive), the same pattern of results is obtained: the increases in arterial pressure are greater in the paired than in each control group, but the heart rate rises to the same extent in all groups. The second study determined that the context in which the responses are tested (conditioning apparatus vs. novel test chamber) does not affect the general pattern of results obtained. The third study demonstrates that the superficially similar increases in heart rate in conditioned and pseudoconditioned rats are achieved by different physiological mechanisms: coactivation of the sympathetic and parasympathetic nervous systems in conditioned rats and sympathetic excitation alone in pseudoconditioned rats. Thus, the heart is influenced by associative emotional processes, but heart rate is not, under these conditions, a particularly useful index of those influences.     

Exploration of cerebellar-dependent associative learning in schizophrenia: effects of varying and shifting interstimulus interval on eyeblink conditioning

Eyeblink conditioning abnormalities have been reported in schizophrenia, but the extent to which these anomalies are evident across a range of delay intervals (i.e., interstimulus intervals; ISIs) is unknown. In addition, the effects of ISI shifts on learning are unknown, though such manipulations can be informative about the plasticity of cerebellar timing functions. Therefore, the primary purpose of the present study was to investigate the interactions between ISI manipulations and learning in schizophrenia. A standard delay eyeblink conditioning procedure with four different interstimulus intervals (ISIs; 250, 350, 550, 850 ms) was employed. Each eyeblink conditioning experiment was immediately followed by another with a different ISI, thus permitting the characterization of conditioned response (CR) learning at one ISI and the extent to which CRs could be generated at a different latency following an ISI shift. Collapsing across all conditions, the schizophrenia group (n = 55) had significantly fewer conditioned responses and longer onset latencies than age-matched controls (n = 55). Surprisingly, shifting to a new ISI had negligible effects on conditioned response rates in both groups. These findings contribute to evidence of robust eyeblink conditioning abnormalities in schizophrenia and suggest impaired cerebellar function, but underscore the need for more research to clarify the source of these abnormalities and their relationship to clinical manifestations of schizophrenia.     

Chronic immobilization stress alters aspects of emotionality and associative learning in the rat

Chronic stress significantly alters limbic neuroarchitecture and function, and potentiates emotionality in rats. Chronic restraint stress (CRS) increases aggression among familiar rats, potentiates anxiety, and enhances fear conditioning. Chronic immobilization stress (CIS) induces anxiety behavior and dendritic hypertrophy in the basolateral amygdala, which persist beyond a recovery period. However, little else is known about the emotional impact of CIS as a model of chronic stress or depression. Therefore, the authors present two experiments examining emotional and learned responses to CIS. In Experiment I, the authors examine individual differences in behaviors during and after CIS, specifically: struggling, aggression, learned helplessness, inhibitory avoidance, and escape behavior. In Experiment II, the authors confirm the effects of CIS on aggression and struggling during immobilization, and correlate individual responses with aspects of conditioned fear. Here the authors report significant effects of CIS on aggression, inhibitory avoidance, escape, as well as learned aspects of fear (i.e., fear conditioning) and inescapable stress (i.e., struggling and helplessness). These results emphasize the emotional and learned responses to CIS evident during and after the stress treatment, as well as the importance of individual differences.     

Ontogeny of eyeblink conditioning in the rat: Auditory frequency and discrimination learning effects

The present study sought to determine whether acoustic properties of the auditory conditioned stimulus (CS) or the use of a discrimination learning procedure would alter the emergence of eyeblink conditioning between postnatal Days 17 and 24 (Days 17–24) in the rat. In Experiment 1, we employed a 3 × 2 × 2 factorial design, involving pitch of the auditory CS (2.8, 5.0, and 9.0 kHz), training condition (paired vs. unpaired), and age (Days 17 or 24). Associative learning was evident at all tone frequencies on Day 24, but increased across frequencies on Day 17, although large age differences in conditioning remained at all tone frequencies. In Experiment 2, rat pups were trained to discriminate 2.8 versus 9.0-kHz tones on Day 17 or Day 24. Eyeblink conditioning increased with tone frequency on Day 24 but discriminative conditioning failed to appear on Day 17. These findings are discussed in relation to the role of auditory system maturation in the ontogeny of eyeblink conditioning. © 1995 Johnv Wiley & Sons, Inc.     

Consider the advantages and disadvantages of microbial examinations in a hospital, and ideal microbial laboratory

The main benefit of carrying out microbial examinations in a hospital is that it rapidly yields information on infectious diseases. Microbiology technicians can easily communicate with the physicians and can carry out precise analyses. The disadvantages are the high costs of microbiological examinations, and the need for long training times for microbial laboratory technicians because of the highly technical nature of their duties. In-hospital microbial inspections will lead to: 1)improved rapid diagnostic tests for infectious diseases and evaluation of antibiotic treatment in the early stages of disease; 2) detection of the precise origin of microbes and confirmation of etiological factors; 3) antibiotic susceptibility testing and evaluation of combined effects of antibiotics against multiple drug-resistant bacteria; and 4)genetic analysis and epidemiological statistical analysis for the purpose of infection control in a hospital and surrounding areas.     

The nitrite/collagen reaction: non-enzymatic nitration as a model system for age-related damage.

The effects of age seen in long-lived connective tissue proteins are thought to be the result of post-translational modifications by reactive molecules. One such molecule is the nitrite ion. Human nitrite exposure results predominately from endogenous production of nitric oxide as well as inhalation of cigarette smoke and ingestion of cured meats. Although nitrite reactions with various proteins have been studied previously with regard to carcinogenesis, the specific reaction with collagen and its role in age-related damage has never been examined. We describe the reaction of nitrite with type I collagen at neutral pH and body temperature. The incubation of collagen with nitrite results in an increase in cross-linking, the accumulation of a yellow chromophore, and a depletion of tyrosine residues. Similar changes also are found in aged human collagen. In addition, 3-nitro-tyrosine, which has recently been used as a marker for peroxynitrite mediated damage, is produced from this reaction. Thus, we propose non-enzymatic nitration as an in vitro model system for human collagen age-related damage.     

Food restriction as a modulator of age-related changes in serum lipids

Fischer 344 male rats were either fed ad libitum or 60% of the ad libitum intake. The restriction of food intake markedly increased the median length of life. Postabsorptive serum cholesterol and phospholipid concentrations increase in the ad libitum-fed rats with increasing age. Life-prolonging food restriction does not influence the serum levels of these lipids in young rats but delays the age-related increase in concentrations. Postabsorptive serum free fatty acid (FFA) concentrations decrease with advancing age in ad libitum-fed rats. Life-prolonging food restriction, while not affecting the serum FFA levels in young rats, delays and possibly partially prevents the age-related decrease in concentration. Food restriction lowers postabsorptive serum triglyceride levels at all ages studied. The data on serum cholesterol, phospholipids, and FFA provide further evidence that food restriction delays age-related changes in the physiological systems of rats. This delay of physiological decline may well retard the occurrence of age-related disease processes, thus prolonging life.     

多媒体课件在生理学教学中的利弊分析与对策

多媒体辅助教学已经广泛应用于生理学教学中。本文通过分析多媒体课件在生理学教学中的利弊与认识误区,研究多媒体课件的制作与应用对策,期望能够达到扬长避短,充分发挥多媒体教学的积极作用,提高生理学教学质量。     

The paradoxical advantages and disadvantages of natural selection: the case history of Charles Darwin

The biology of natural selection is an enduring mystery, as is the nature of Charles Darwin's chronic illness. Of the theories advanced to explain the latter, Oedipal conflicts and Chagas' disease are preeminent. Hypomania, however, propelled Darwin to the pinnacle of scientific achievement and good health, the depression that followed condemning him to intellectual stagnation, lethargy, impaired memory and concentration, and incapacitating gastrointestinal disorders. Examples of natural selection in humans are much sought after when, ironically, one need look no further than Darwin himself.     

The new Vienna classification of epithelial neoplasia of the gastrointestinal tract: advantages and disadvantages

A number of seminars have shown considerable differences between Japanese and Western pathologists in the diagnostic differentiation of reactive changes, dysplasia and well-differentiated adenocarcinoma in gastroenterological biopsy material. Lesions that most Western pathologists identify as "dysplasia" are often considered adenocarcinomas in Japan. A comparison of the biopsy-based diagnoses with those established in resected mucosa, however, reveals appreciable diagnostic inexperience on the part of Western pathologists, with significant discrepancies between their diagnoses based on biopsies and those based on resected material. Against this background, a new classification of epithelial neoplasia of the gastrointestinal tract was drafted on the occasion of the World Congress of Gastroenterology in Vienna in 1998. By collapsing the diagnoses "high-grade adenoma/dysplasia, noninvasive carcinoma (carcinoma in situ), and suspected invasive carcinoma" into a single category ("noninvasive high-grade neoplasia", category 4), this scheme should largely eliminate the diagnostic discrepancies between Western and Japanese pathologists. As with every classification, the Vienna classification has its advantages and disadvantages; these are discussed here. The most important advantage of the Vienna classification is that the various categories are associated with different recommendations for further diagnostic and therapeutic measures. This applies in particular to category 4, with the recommendation for only local treatment initially (endoscopic mucosal resection or surgical excision). Since the introduction of the Vienna classification, the new World Health Organization classification of neoplasia of the gastrointestinal tract has recently been published, in which the term dysplasia has been replaced by "intraepithelial neoplasia". This means that the Vienna classification needs to be modified accordingly.     

Studies of age-related changes in the metabolism of eosin in the rat.

Male rats of different age groups maintained normally on laboratory chow were injected with eosin (2,4,5,7-tetrabromo-11-carboxyfluorescein) after which the biliary excretion of the dye was studied. In 3 age groups below 42 weeks, the dye was excreted as 2 compounds which were identified by thin-layer chromatography as unchanged eosin (Rf 0.90--0.91) contributing about 80--90% and one conjugated compound of Rf 0.43--0.47 (14--9%) which was shown to be a glucuronide. Eosin metabolites could not be traced in 30 and 42 week-old rats. This finding is discussed in relation to: (i) age and enzymic activity, and (ii) bio-activated metabolites of this dye which may induce biochemical or toxicological and carcinogenic lesions.     

Hand digit control in children: age-related changes in hand digit force interactions during maximum flexion and extension force production tasks

We studied the finger interactions during maximum voluntary force (MVF) production in flexion and extension in children and adults. The goal of this study was to investigate the age-related changes and flexion–extension differences of MVF and finger interaction indices, such as finger inter-dependency (force enslaving (FE): unintended finger forces produced by non-instructed fingers during force production of an instructed finger), force sharing (FS; percent contributions of individual finger forces to the total force at four-finger MVF), and force deficit (FD; force difference between single-finger MVF and the force of the same finger at four-finger MVF). Twenty-five right-handed children of 6–10 years of age and 25 adults of 20–24 years of age participated as subjects in this study (five subjects at each age). During the experiments, the subjects had their forearms secured in armrests. The subjects inserted the distal phalanges of the right hand into C-shaped aluminum thimbles affixed to small force sensors with 20° of flexion about the metacarpophalangeal (MCP) joint. The subjects were instructed to produce their maximum isometric force with a single finger or all four fingers in flexion or extension. In order to examine the effects of muscle–force relationship on MVF and other digit interaction indices, six subjects were randomly selected from the group of 25 adult subjects and asked to perform the same experimental protocol described above. However, the MCP joint was at 80° of flexion. The results from the 20° of MCP joint flexion showed that (1) MVF increased and finger inter-dependency decreased with children’s age, (2) the increasing and decreasing absolute slopes (N/year) from regression analysis were steeper in flexion than extension while the relative slopes (%/year) with respect to adults’ maximum finger forces were higher in extension than flexion, (3) the larger MVF, FE, and FD were found in flexion than in extension, (4) the finger FS was very similar in children and adults, (5) the FS pattern of individual fingers was different for flexion and extension, and (6) the differences between flexion and extension found at 20° MCP joint conditions were also valid at 80° MCP joint conditions. We conclude that (a) the finger strength and independency increase from 6 to 10 years of age, and the increasing trends are more evident in flexion than in extension as indexed by the absolute slopes, (b) the finger strength and finger independency is greater in flexion than in extension, and (c) the sharing pattern in children appears to develop before 6 years of age or it is an inherent property of the hand neuromusculoskletal system. One noteworthy observation, which requires further investigation, was that FE was slightly smaller in the 80° condition than in the 20° condition for flexion, but larger for extension for all subjects. This may be interpreted as a greater FE when flexor or extensor muscles are stretched.     

Antineutrophil cytoplasmic antibody measurement: advantages and disadvantages of a capture PR3 ELISA and a direct PR3 ELISA

AIM: To compare the performance of a capture proteinase 3 enzyme linked immunosorbent assay (PR3 ELISA) with a direct PR3 ELISA in the measurement of PR3 antineutrophil cytoplasmic antibodies (ANCA). METHOD: The performance of both assays systems was compared using two sets of sera. Sera from patients (n = 49) suffering from Wegener's granulomatosis (WG) and fulfilling the American College of Rheumatology classification criteria (or a modification of those criteria that allowed for ANCA positivity) were used along with sera from a group of patients (n = 48) considered to have a clinically false positive PR3 ANCA result when measured by routine direct ELISA. RESULTS: Using the assay specific cut-offs, the direct ELISA gave a positive result in 92% on repeat testing and the capture ELISA a positive result in 84% of sera from patients with WG. The capture ELISA was negative in 75% of patients considered to have a false positive PR3 ANCA on initial testing by direct ELISA (27% were negative on repeat testing by direct ELISA). The mean concentration of PR3 ANCA in WG patient sera measured by the capture ELISA was significantly higher than that measured by the direct ELISA. The capture PR3 ELISA had a broader analytical range which was also reflected in PR3 ANCA concentrations measured in serial serum samples from WG patients. CONCLUSION: In this study the direct PR3 ELISA performed better as a screening test for PR3 ANCA compared with the capture PR3 ELISA, mainly because the cut-off for the capture ELISA needed to be set higher to avoid non-specific binding. In contrast, the improved analytical range of the capture ELISA made it a potentially more useful method for monitoring serial PR3 ANCA concentrations. In specific serum samples the capture ELISA was better able to discriminate 'false positive' PR3 ANCA.     

Age-related changes of serotonin and its metabolites content in the visual system of the rat

Measurements have been taken of the serotonin and its metabolites (tryptophan, 5-hydroxytryptophan, 5-hydroxy-3-indolacetic acid and 5-hydroxytryptophol) in each structure of the geniculate and extrageniculate visual system of rats aged between 3 and 30 months. The concentration of tryptophan was the highest of all compounds studied. Its increase during ageing is statistically significant in the lateral geniculate and posterior thalamus. 5-HTP concentration was very low and in some cases not detectable. 5-HT concentrations and its principal metabolite, 5-HIAA, showed a different profile in each brain structure. The lateral geniculate and visual cortex showed statistically significant changes, but with opposite results. In the lateral geniculate the 5-HT and 5-HIAA concentrations were increased during the ageing period. However, in the visual cortex the 5-HT and 5-HIAA concentrations decreased in the same period. These age-related changes were not seen in the superior colliculus and posterior thalamus as in the 5-HT levels as in the 5-HIAA. 5-hydroxytryptophol was always found in low concentration. These results suggest age-related changes in the geniculate visual system.     

Classical conditioning of the flexion reflex in spinal cat: features of the reflex circuitry

A technique has been developed to investigate sodium-independent L-[3H]glutamate binding in rat brain sections using quantitative autoradiography and tritium-sensitive film. Binding is rapid (reaching equilibrium in 5 min) and reversible (having a t 1/2 of dissociation of 0.38 min). Glutamate apparently bound to a single population of sites with a Kd of about 1.0 microM. The pharmacology of this binding site is similar to that observed in homogenate studies. There is marked regional variation in the amount of glutamate bound. Of the areas analyzed in detail, the density of sites is greatest in stratum moleculare of hippocampus, followed by striatum and cortex.