Inheritance of spatial learning ability in inbred mice: a classical genetic analysis.

The inheritance of spatial learning ability in inbred mice was examined by performance of a classical genetic cross between the 2 inbred strains C57BL/6Ibg and DBA/2Ibg. The inbreds were crossed to produce the 1st filial generation (F1) hybrids. F1 mice were bred to each other and were backcrossed to the parental strains to produce 3 hybrid generations with recombinant genotypes. The animals were tested for spatial learning ability in the Morris water task. All hybrid generations showed greater spatial learning ability than the inbreds, with F1 hybrids showing the greatest degree of spatial learning. The inheritance pattern for spatial learning differed between male and female mice, with males showing a type of inheritance in which dominant genes made the major contribution to the expression of the behavior. Females showed equal contributions of dominance deviation and additive genetic effects. The results are discussed in terms of fitness value to the animals.

Haloperidol and clonidine increase, and apomorphine decreases ultrasonic vocalizations by gerbils.

Ten psychotropic drugs that have putative effects on central brain neurotransmitters were assessed for influences on ultrasonic signaling relative to general activity in male Mongolian gerbils. Haloperidol (1 mg/kg IP), a dopamine antagonist, and clonidine (0.1 mg/kg IP), a norepinephrine agonist, increased ultrasonic signaling, and apomorphine (5 mg/kg IP), a dopamine agonist, decreased ultrasonic signaling. Catecholamines may modulate ultrasonic signaling in the gerbil. Body temperature changes were positively with ultrasonic emission in tests after saline, haloperidol, apomorphine, and 5-hydroxytryptophan (30 mg/kg IP).

Effects of N-methyl-D-aspartate antagonism on spatial learning in mice.

C57BL/6Ibg mice were treated with the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and tested for selective deficits in spatial learning ability in the Morris water task. Two types of training protocols were used during the initial exposure to the training environment. In protocol 1, animals were given four massed trials before being returned to their home cages. In protocol 2, animals were returned to their home cages after each of the first four trials. Following the initial four trials, both sets of animals were given massed trials in blocks of four. CPP had minor effects on nonspatial learning, with greater impairment seen in animals trained according to protocol 1 than in animals trained according to protocol 2. The drug increased latency to find the platform in the spatial learning form of the task, with no effect of training protocol on latency. When spatial learning ability was measured in terms of the search behavior exhibited by the animals after the platform was removed from the pool, animals trained according to protocol 1 showed a severe CPP-induced impairment in search accuracy. Animals trained according to protocol 2 showed no effect of drug treatment. The results suggest that CPP does not have a reliable effect on place learning and that factors other than the type of learning being tested may contribute to performance deficits following CPP treatment.

Hippocampal protein kinase C activity is reduced in poor spatial learners.

Activation of protein kinase C (PKC) via neurotransmitter coupling processes has been associated with long-term potentiation (LTP) or classical conditioning, but whether natural variation in PKC activity affects learning performance remains to be determined. Inbred strains of mice differ in their ability to exhibit spatial reference memory as measured by the Morris water task. C57BL/6Ibg (C57) mice perform the task better than DBA/2Ibg (DBA) mice, which show relatively little spatial preference. Hippocampal PKC activity extracted from the particulate fraction was lower in DBA mice than in C57 mice. To examine the potential relationship of PKC activity with spatial learning performance, 11 C57BL/6J x DBA/2J recombinant inbred strains (BXD RIs) were trained in the place learning version of the Morris water task. Cortical and hippocampal PKC activities were measured. Variation in spatial learning performance and PKC activity from cortex and hippocampus was observed. A positive significant correlation was observed between measures of spatial learning accuracy and hippocampal PKC in these strains. No correlation was observed between spatial learning accuracy and cortical PKC activity. These data suggest that animals with lower hippocampal PKC activity may have problems performing spatial reference memory tasks with the same degree of accuracy as those with higher hippocampal PKC activity.

Reactive capacity: a sensitive behavioral marker of movement initiation and nigrostriatal dopamine function.

Thirty-two Long Evans male rats with sham operations or unilateral 6-OHDA-induced damage to meso-telencephalic dopaminergic neurons were evaluated on a reactive capacity task that demanded high speed movement initiation. The task required lever manipulation to avoid signalled shock. The interval between the warning and the shock was incrementally reduced. A one-sleeved vest provided the opportunity to measure movement initiation of each limb independently. Extent of lesion was assessed by [3H]DA uptake, [3H]spiroperidol binding, or DA levels. Movement initiation latencies for each forelimb were found to be linearly related to interhemispheric striatal DA asymmetry induced by microinjections of 6-OHDA. Even those lesions resulting in small to moderate decreases in DA function, including deficits causing no chronic posture or sensory asymmetries, resulted in reactive capacity deficits and greatly slowed reaction time in the paw contralateral to the lesion. Following severe lesions, small yet substantial deficits were also seen in ipsilateral paw performance, which may be related to DA depletions found in the non-lesioned striatum. Thus, a reactive capacity task which requires the animal to react with maximal speed appears to be a potentially good index of nigrostriatal dopamine integrity even when the depletion is not severe.

Evidence for species differences between rats and gerbils in striatal dopamine content and dopamine metabolism.

High-performance liquid chromatography revealed significantly higher striatal concentrations of dopamine and homovanillic acid (HVA) in 9 male Mongolian gerbils than in 6 male Long-Evans rats. 5-Hydroxyindoleacetic acid concentrations were higher in rats, while no significant between-species difference was found with respect to 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin or protein concentrations. In gerbils, HVA and DOPAC occurred in approximately equal concentrations, suggesting that the formation of HVA may be of greater significance for the termination of transmitter function in the gerbil than in the rat.

Heterosis and resistance to DFP effects on spatial learning in C57BL X DBA hybrids.

The inbred mouse strains C57BL/6Ibg and DBA/2Ibg differ in their ability to exhibit spatial learning in the Morris water task. C57BL mice learn the task well and show impairment of spatial learning following disruption of cholinergic function. DBA mice show rudimentary spatial learning ability, and are not further impaired when cholinergic function is decreased. These mice may carry genes regulating a noncholinergic spatial learning system. To test this hypothesis, first generation (F1) hybrids between DBA and C57BL mice were tested for spatial learning in the Morris water task. The hybrids performed better than either parental strain, suggesting that both parents contributed genes for spatial learning ability. Chronic treatment with diisopropylfluorophosphate (DFP), which abolished spatial learning ability in C57BL mice, produced only minor impairments in the hybrids. The behavioral resistance to DFP occurred despite significant reductions in hippocampal and cortical muscarinic binding. The results suggest either that the hybrids inherited a noncholinergic neurochemical system influencing spatial learning from their DBA parents or that the DFP treatment did not disrupt cholinergic function to a sufficient degree to impair the superior learning abilities of the F1 hybrids.

Carbon monoxide exposure potentiates high-frequency auditory threshold shifts induced by noise.

Hypoxia has long been hypothesized to play a role in noise-induced hearing loss, and the disruption of auditory function by asphyxiation has been repeatedly demonstrated. Recent data, however, suggest that the cochlea is resistant to less extreme hypoxic events. The current report describes the combined effects of noise and hypoxia on a measure of auditory function, in an effort to clarify the role of hypoxia in hearing loss. Exposure to 1200 parts per million of carbon monoxide in air for 90 min preceding and 120 min concurrent with exposure to a broad-band noise at 110 dBA produced high-frequency threshold shifts of greater magnitude than those produced by exposure to noise alone. An equivalent carbon monoxide exposure in a 'quiet' environment did not produce any change in auditory detection thresholds. The potentiation of noise-induced threshold shifts by carbon monoxide provides additional support for the hypothesized role of metabolic exhaustion or bloodflow impairment in noise-induced hearing loss. It also suggests a possible interpretation of clinical findings of auditory impairment associated with carbon monoxide exposure.

Effects of chronic diisopropylfluorophosphate treatment on spatial learning in mice.

The Morris water task was used to measure the effects of chronic diisopropylfluorophosphate (DFP) treatment on C57BL/6Ibg mice. Control mice showed good task acquisition and searched accurately for the platform after it was removed from the pool, suggesting that they had formed a spatial map of the platform's location relative to distal cues. In contrast, mice chronically treated with DFP prior to training showed a marked deficit in spatial learning. Chronic DFP treatment did not affect ability to locate a visible platform and did not impair task retention in mice trained to find the hidden platform prior to DFP treatment. The chronic DFP treatment decreased muscarinic binding in cortex, hippocampus, and striatum. These results indicate that C57BL mice are capable of spatial learning in the water task. The ability of chronic DFP treatment to impair place but not cue learning suggests that the cholinergic dysfunction produced by DFP is similar to those produced by lesions of central cholinergic systems and acute treatments with muscarinic antagonists.

The effects of chronic oxotremorine treatment on spatial learning and tolerance development in mice.

C57BL mice were treated with 0.5 mg/kg/hr oxotremorine through an implanted subcutaneous cannula for 6 days. Tolerance to oxotremorine was evaluated after treatment by constructing cumulative dose-response curves and measuring body temperature and rotarod performance. At 2 hr after removal, mice exhibited a 15-fold tolerance as measured by body temperature and a 4-fold tolerance as measured by rotarod performance. This tolerance as measured by body temperature was lost by two days after removal from treatment. Immediately after treatment, 3H-QNB binding was reduced in cortex, hippocampus, midbrain, hindbrain, and hypothalamus. Receptors returned to normal within 4 to 8 days after cessation of treatment depending on the brain region. Spatial learning was examined using the Morris water task. Mice that began their training in this task 1 day after they were removed from oxotremorine treatment were impaired in their spatial ability as evidenced by a lack of preference for the trained site during a probe trial. Mice that began their training 2 days after cessation of oxotremorine treatment showed no evidence of impairment in spatial learning. These results suggest that a loss of muscarinic receptors after oxotremorine treatment can be dissociated from tolerance loss and spatial learning deficits.

DBA/2Ibg mice are incapable of cholinergically-based learning in the Morris water task.

In comparison to C57BL/6Ibg mice, DBA/2Ibg mice are slow to find a submerged platform in the Morris water task. Spatial learning in this task is known to be severely disrupted by treatments that reduce muscarinic cholinergic function. DBA mice were chronically treated with diisopropylfluorophosphate (DFP) in order to decrease muscarinic binding in the brain. Despite significant losses of binding sites in cortex, midbrain, hindbrain, hippocampus, and striatum, the mice failed to show an effect of DFP treatment on latency to reach the platform. Saline-treated DBA mice showed only marginal preference for searching the appropriate region of the pool during a probe trial in which the platform was absent from the pool. The pattern of search behavior was not altered by DFP treatment. These data are in strong contrast to data obtained previously with C57BL/6Ibg mice, which show accurate search behavior that is completely disrupted by DFP treatment. DBA mice thus appear incapable of true, cholinergically-mediated spatial learning. It is hypothesized that these mice lack normal function of the septo-hippocampal system.

Posture-independent sensorimotor analysis of inter-hemispheric receptor asymmetries in neostriatum.

Nigrostriatal dopaminergic neurons are thought to be critically important for somato-sensorimotor behavior. Following unilateral irreversible elimination of these neurons, an animal shows an ipsiversive postural bias and permanently fails to orient its head toward tactile stimuli placed on the contralateral side of the body. In response to apomorphine, a dopamine agonist, these rats display contraversive circling. This effect is thought to reflect denervation-induced proliferation of dopamine receptors in the ipsilateral striatum. We have developed a sensitive procedure that measures sensorimotor function independent of postural and circling biases. We record the latencies to remove small pieces of adhesive stimuli placed onto the snout or radial surface of the forelimbs. The stimuli are placed symmetrically and simultaneously, which is analogous to tactile-extinction procedures used clinically. In the first study we found that rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal pathway showed a contralateral sensorimotor bias in response to doses of apomorphine below those necessary to produce contraversive circling. In a second study, unilateral striatal microinjections of kainic acid (KA) were used to destroy the neurons on which the postsynaptic dopaminergic receptors of the nigrostriatal system are contained. Compared to 6-OHDA, KA produced unexpected results in standard orientation tests. None of the KA-treated rats showed contralateral neglect, and some even showed ipsilateral deficits. However, the standard orientation tests are confounded by postural asymmetries, which were irregular in the KA-treated group. Using again the posture-independent sensorimotor procedure, we found that all KA-treated rats, like the 6-OHDA-treated rats, uniformly displayed ipsilateral sensorimotor biases. Sensorimotor function relating to inter-striatal asymmetries may be more specifically assessed with the bilateral-adhesive tests.

Is anonymity important in AIDS survey research?

In two experiments, findings with college undergraduates (Ns = 154 and 137) suggest social desirability may not affect responses to survey items on HIV-related behaviors and results may not be constrained by anonymity.

A behavior analysis of the offspring of "haloperidol-sensitive" and "haloperidol-resistant" gerbils.

The first generation (F1) offspring of haloperidol-sensitive (HS) and haloperidol-resistant (HR) gerbils were compared in a battery of motor ("catalepsy") tests, a novel cardboard-shredding (oro-facial stereotypy) test, and a holeboard (exploration) test. The F1 HS gerbils were more "cataleptic" than the F1 HR gerbils after haloperidol (1 and 3 mg/kg). The F1 HR gerbils showed more oro-facial stereotypy and more exploratory behavior than did F1 HS gerbils in undrugged tests. The F1 HS and F1 HR groups did not differ in "general activity" as measured by line crossings in an open field or by an electromagnetic monitor in the home cage. These results are preliminary behavioral evidence for a difference between HS and HR gerbils in dopaminergic or related functions.

Values and nursing home life: how residents and care givers compare.

Do you and your staff know exactly what your residents want from your facility? This study compares residents' top ten concerns with what their administrator and staff think their top concerns.