The elevated plus and zero mazes (Plus and Zero, respectively) are used to assess behavior related to anxiety in rodents but direct comparisons of the two tests are lacking for rats. We compared the two methods in adult male Sprague-Dawley rats. Untreated rats in the Zero spent more time in open zones and exhibited more head dips than in the Plus whereas start latency and closed area entries were lower in the Zero than in the Plus. Diazepam (1 mg/kg) exposure increased time in the open in both mazes. Restraint (60 min prior to testing), yohimbine (2.5 mg/kg), and caffeine (100 mg/kg) had the opposite effect, significantly decreasing time spent in open zones in both mazes. No sexual dimorphism in behavior was seen in either maze in untreated rats. Although more open area time was evident in untreated animals in the Zero, after drug challenge both mazes detected anxiolytic and anxiogenic effects equally. Zero maze data can be analyzed directly because no center region exists; otherwise the two methods appear comparable following challenge.
Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague-Dawley rats from E14-18 with 8 mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) groups) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light-dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that, degree of maternal immune activation predicts severity of effects on offspring behavior.
Successful navigation requires interactions among multiple but overlapping neural pathways mediating distinct capabilities, including egocentric (self-oriented, route-based) and allocentric (spatial, map-based) learning. Route-based navigation has been shown to be impaired following acute exposure to the dopaminergic (DA) drugs (+)-methamphetamine and (+)-amphetamine, but not the serotoninergic (5-HT) drugs (±)-3,4-methylenedioxymethamphetamine or (±)-fenfluramine. The dopaminergic-rich neostriatum is involved in both allocentric and egocentric navigation. This experiment tested whether dorsal striatal DA loss using bilateral 6-hydroxydopamine (6-OHDA) injections impaired one or both types of navigation. Two weeks following 6-OHDA injections, rats began testing in the Cincinnati water maze (CWM) followed by the Morris water maze (MWM) for route-based and spatial navigation, respectively. 6-OHDA treatment significantly increased latency and errors in the CWM and path length, latency, and cumulative distance in the MWM with no difference on cued MWM trials. Neostriatal DA levels were reduced by 80% at 2 and 7 weeks post-treatment. In addition, 6-OHDA increased DA turnover and decreased norepinephrine (NE) levels. 6-OHDA injections did not alter monoamine levels in the prefrontal cortex. The data support that neostriatal DA modulates both types of navigation.
Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero-maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, acoustic startle, or latent inhibition deficits reported in Poly IC-treated rats, but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).
Rats treated with (+)-methamphetamine (MA) on postnatal (P) days 11−20 exhibit long-term spatial and path integration (Morris and Cincinnati water mazes) learning deficits whereas those treated on P1−10 do not. MA-treatment increases corticosterone release in an age-dependent U-shaped pattern that corresponds to the stress hyporesponsive period (SHRP; P4−15). Here we tested the hypothesis that the cognitive effects induced by MA are associated with treatment that begins within the SHRP. Three treatment regimens were compared, P1−10, 6−15, and 11−20. One male/female pair/litter received 0, 10, or 25 mg/kg MA/dose (4 doses/day at 2 h intervals given s.c. with 19−21 litters/ regimen). Locomotor activity and acoustic startle were tested as behaviors not predicted to be associated with the SHRP. Cincinnati and Morris water maze findings were consistent with the hypothesis in that MA-treated animals exposed from P6−15 or P11−20 showed impaired learning compared to those exposed from P1−10; however, on probe trials in the Morris water maze, MAinduced memory impairments were not regimen-specific and were contributed to by all treatment regimens. All MA treatment regimens induced reductions in locomotor activity and acoustic startle facilitation as expected. No differential effect on prepulse trials was seen suggesting no impairment in sensory gating. Cognitive deficits from neonatal MA treatment are associated with the SHRP and may be the product of hypothalamic-pituitary-adrenal axis dysregulation during critical periods of brain development.
Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of ‘active’ maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6 h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1 h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function.
Despite restrictions, exposure to lead (Pb) continues. Moreover, exposure varies and is often higher in lower socioeconomic status (SES) families and remains a significant risk to cognitive development. Stress is another risk factor. Lower SES may be a proxy for stress in humans. When stress and Pb co-occur, risk may be increased. A few previous experiments have combined Pb with intermittent or acute stress but not with chronic stress. To determine if chronic developmental stress affects outcome in combination with Pb, we tested such effects on growth, organ weight, brain monoamines, and response to an acute stressor. Sprague Dawley rats were gavaged with Pb acetate (1 or 10 mg/kg) or vehicle every other day from postnatal day (P)4-29 and reared in standard or barren cages. Subsets were analyzed at different ages (P11, 19, 29). Chronic stress did not alter blood Pb levels but altered HPA axis response during early development whereas Pb did not. Pb treatment and rearing each altered organ to body weight ratios, most notably of thymus weights. Both Pb and rearing resulted in age-and region-dependent changes in serotonin and norepinephrine levels and in dopamine and serotonin turnover. The model introduced here may be useful for investigating the interaction of Pb and chronic developmental stress.
Both egocentric route-based learning and spatial learning, as assessed by the Cincinnati water maze (CWM) and Morris water maze (MWM), respectively, are impaired following an 80% dopamine (DA) loss in the neostriatum after 6-hydroxydopamine (6-OHDA) administration in rats. The dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) are implicated in different navigational learning types, namely the DLS is implicated in egocentric learning while the DMS is implicated in spatial learning. This experiment tested whether selective DA loss through 6-OHDA lesions in the DMS or DLS would impair one or both types of navigation. Both DLS and DMS DA loss significantly impaired route-based CWM learning, without affecting spatial or cued MWM performance. DLS 6-OHDA lesions produced a 75% DA loss in this region, with no changes in other monoamine levels in the DLS or DMS. DMS 6-OHDA lesions produced a 62% DA loss in this region, without affecting other monoamine levels in the DMS or DLS. The results indicate a role for DA in DLS and DMS regions in route-based egocentric but not spatial learning and memory. Spatial learning deficits may require more pervasive monoamine reductions within each region before deficits are exhibited. This is the first study to implicate DLS and DMS DA in route-based egocentric navigation.
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