Behavioral effects of corpus callosum transection and environmental enrichment in adult rats

A common assumption about the corpus callosum transection (CCX) is that it only affects behaviors heavily relying on interhemispheric communication. However, cerebral laterality is ubiquitous across motor and perceptual, cognitive and emotional domains, and the corpus callosum is important for its establishment. Several recent studies showed that the partial denervation of the sensorimotor isocortex through CCX derepressed neural growth processes that were sensitive to motor demand (experience-dependent neural plasticity). We investigated whether the facilitatory effects of CCX on cortical neural plasticity, shaped by differential housing, extended beyond the motor domain. Adult rats were housed in enriched (EE), standard (SE) or impoverished environments (IE) for 10 weeks, that is, 2 weeks before they underwent CCX or sham surgery, and, then, 8 weeks throughout the experiments. After they recovered from surgery, the behavioral performance of rats was tested using open-field, spontaneous alternation in the T-maze, paw preference, Morris water maze, and tone fear conditioning. The results indicated that the effects of CCX and housing on open-field behavior were independent, with CCX increasing the time spent in the center of the field at the beginning of the observation (i.e., emotionality), and EE and IE increasing rearing (emotionality) and reducing teeth-chattering (habituation), respectively. CCX reduced the frequency of spontaneous alternation, denoting spatial working memory deficits, while housing did not influence this performance. Neither CCX, nor housing significantly affected paw preference lateralization, although CCX was associated with a leftward bias in paw preference. In the Morris water maze, housing had effects on spatial acquisition, while CCX reduced activity, without interfering with spatial memory. CCX did not influence tone fear conditioning, but context fear conditioning seemed to benefit from EE. We conclude that CCX in adult rats has subtle, but specific behavioral effects pertaining to emotionality, spatial working memory, and, possibly, aversively motivated exploration, and these effects are either independent or only peripherally interact with the effects of housing.     

The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats

1. The Emergence Test (ET), a variation of the open field test in which the rat is not handled, and is purported to measure neophobia, was applied to Wistar Kyoto (WKY) and Sprague Dawley (S-D) rats.

2. While no-stress control WKY rats were less active in the ET, pre-treatment with shock stress exacerbated strain differences. WKY rats, previously exposed to shock, did not emerge from the home cage start box during repeated testing, whereas previously stressed S-D rats vacated the home cage quickly and revealed increasing behavioral agitation.

3. Diazepam reduced emergence latency only in S-D rats, whereas nomifensine significantly increased head poke responses in WKY rats.

4. WKY rats responded to the ET with characteristically depressive behavior, whereas S-D rats responded to the same ET with behavioral agitation and anxiety. The implications of these behavior patterns for discriminating between anxiety and depressive behavior are presented.

Behavioral variability, elimination of responses, and delay-of-reinforcement gradients in SHR and WKY rats

Background  

Attention-deficit/hyperactivity disorder (ADHD) is characterized by a pattern of inattention, hyperactivity, and impulsivity that is cross-situational, persistent, and produces social and academic impairment. Research has shown that reinforcement processes are altered in ADHD. The dynamic developmental theory has suggested that a steepened delay-of-reinforcement gradient and deficient extinction of behavior produce behavioral symptoms of ADHD and increased behavioral variability.     

Effect of environmental enrichment on stress related systems in rats

The aim of this study was to test whether environmental enrichment alters the status and responsiveness of pituitary-adrenocortical and sympathetic-adrenomedullary hormones in rats. Previous studies have shown that rats kept in an enriched environment differ from those kept in standard cages in dendritic branching, synaptogenesis, memory function, emotionality and behaviour. In male Wistar rats kept in an enriched environment for 40 days, we studied basal concentrations of hormones, endocrine responses to 5-HT(1A) challenge and responsiveness and adaptation to repeated handling. Environmental enrichment consisted of large plexiglass cages with 10 rats per cage, which contained variety of objects exchanged three times a week. Rats kept in this enriched environment had higher resting plasma concentrations of corticosterone, larger adrenals and increased corticosterone release to buspirone challenge compared to controls. Lower adrenocorticotropic hormone, corticosterone and adrenaline responses to handling were noticed in rats kept in an enriched environment. Exposure to repeated handling led to a more rapid extinction of corticosterone responses in rats kept in an enriched environment. Thus, environmental enrichment leads to pronounced changes in neuroendocrine regulation, including larger adrenals and increased adrenocortical function, which are so far considered to be indication of chronic stress.     

Behavioral effects of deprenyl in aged rats

The effects of an inhibitor of MAO-B, deprenyl, have been studied in aged male rats. Subcutaneous (s.c.) injection of deprenyl was followed by a facilitated acquisition of active avoidance behavior and a facilitated retention of passive avoidance response in a dose-dependent manner. Ambulation and rearing of aged rats in an open field were increased by deprenyl. No effect was found on grooming behavior. Apomorphine-induced stereotypies were potentiated and haloperidol-induced catalepsy was inhibited by deprenyl. Some elements of sexual behavior, i.e. latency to mounting and intromission and frequency of mounts and intromissions, were improved by deprenyl. Furthermore, deprenyl reduced the immobility of aged rats in a "despair" test, suggesting an antidepressant activity. Deprenyl seems to be effective in correcting some of the behavioral deficits of aged animals. Its behavioral effects can be related to the inhibition of cerebral MAO-B.     

Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats

Evidence was found for different outcomes to middle cerebral artery occlusion in the young genetically hypertensive stroke-prone rat (SHRSP) compared to sham operated controls and the Wistar Kyoto rat (WKY). Qualitatively and quantitatively different gross lesions marked by Evans blue-albumin, cortical atrophy, large areas of strikingly altered cortical histology, postoperative survival and motor behavioral deficits differentiate young SHRSP from sham operated controls and the normotensive WKY. We conclude that the limited focal lesion observed in normotensive and sham operated rats is primarily due to surgical trauma of exposing the vessel and passing the ligature deep to it. The grossly larger and qualitatively different lesion in the SHRSP is the result of an inadequate circulation provided by the dorsal cerebral arterial collaterals. Since the 5-6 week old SHRSP were only mildly hypertensive (systolic blood pressure 140 mm Hg), the inadequate collateral circulation appears to be related to either a genetic or acquired problem rather than being secondary to a vascular lesion of chronic hypertension.     

Behavioural and glial changes in old rats following environmental enrichment.

The effects of enriched environment on short-term memory for event durations and on astrocytes (cell density, cell area and % of GFAP immunoreactivity) in hippocampus (Hi), frontal cortex (FC) and corpus callosum (CC) were analysed in old rats housed from weaning to the end of behavioural testing (23 months) either in standard (SC) or in enriched (EC) conditions and in young adults (5 months) all housed in SC. Old SC and EC and young SC rats trained (for 2 months) or not, in a Symbolic Delayed Matching to Sample Task, had to discriminate and remember two (2- and 10-s) signals after short retention intervals. Results confirm the aging-related acquisition and memory deficit. EC reduced the slowness of acquisition, reversed the short-term memory deficit and promoted the retention of the short signal (choose short effect). Old SC naive rats had many hypertrophied astrocytes with long processes in Hi and CC while old EC rats had decreased astrocytes number and size. The behavioural testing resulted in young adult SC rats in Hi and CC, in increased astrocytes number, size and GFAP% and in their decrease in old SC rats. EC and testing have additive effects (very low astrocytes number, size and GFAP%) to compensate for the aging-induced gliosis, mostly in Hi.     

Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats

Postinjury environmental enrichment (EE) has been shown to alter functional and anatomical outcomes in a number of injury paradigms, including traumatic brain injury (TBI). The question of whether EE alters functional outcome following TBI in a model which produces overt histopathological consequences has not been addressed. We investigated this question using the severe, parasagittal fluid percussion injury (FPI) model. Rats (n = 7 per group, enriched and standard for behavior; n = 15 per group for histology) underwent severe (2.2-2.6 atm) FPI, with sham-operated rats (n = 7 per group, enriched and standard for behavior; n = 6 enriched, n = 3 standard for histology) serving as controls. Animals were allowed to recover for 11 days either in standard single housing or together (injured and sham) in an enriched environment consisting of a 92 x 61 x 77-cm ferret cage filled with various stimulatory objects. Consistent with earlier reports, injured animals recovering in the enriched environment showed significantly (P < 0.05) shorter latencies to find the platform in a Morris Water Maze task versus injured/standard animals on day 12 post-TBI. However, both injured groups showed significant deficits versus sham groups (P < 0.05). There were no differences between the sham/enriched and sham/standard groups. No significant group differences in swim speed were observed. At 14 days post-TBI, enriched animals had approximately twofold smaller lesion areas in regions of the cerebral cortex posterior to the injury epicenter (-4.5, -5.8, -6.8 mm relative to bregma; P < 0.05) compared to injured/standard animals. In addition, overall lesion volume for the entire injured cortical hemisphere was significantly smaller in animals recovering in the enriched environment. These results indicate that noninvasive environmental stimulation is beneficial in attenuating cognitive deficits and preserving tissue integrity in a TBI model which causes cerebral contusion and cell death.     

The effects of environmental enrichment in the chick anxiety-depression model

As a validation step of an animal simulation, the effects of environmental enrichment were tested in the anxiety-depression model, in which socially raised chicks are placed in isolation for a 2 h test period. Isolated chicks display an initial high rate of distress vocalizations, constituting the anxiety-like phase, followed by a marked decline and plateau in rates of vocalizations for the remainder of time in isolation, characterizing the depression-like phase. Four separate groups of domestic fowl chicks were group housed under enriched, impoverished (i.e., non-enriched) or a combination of the two housing conditions for six days and tested at 7 d posthatch in the aforementioned isolation procedure. Rates of distress vocalizations in the anxiety-like (2-3 min) or depression-like (30-120 min) phases were not affected by housing conditions. However, chicks continuously housed in enriched environments and chicks housed in the enriched environments on days 4-6 displayed a delay in the onset of the depression-like phase. The beneficial effect of environmental enrichment on the depression-like phase is consistent with other stress paradigms and provides another step towards validating the chick anxiety-depression model as a clinical simulation.     

Impulsive choice and environmental enrichment: effects of d-amphetamine and methylphenidate

Individual differences in impulsive choice and rearing in differential environments are factors that predict vulnerability to drug abuse. The present study determined if rearing influences impulsive choice, and if d-amphetamine or methylphenidate alters impulsive choice in differentially reared rats. Male Sprague-Dawley rats were raised from 21 days of age in either an enriched condition (EC) or an isolated condition (IC) and were tested as young adults on an adjusting delay task. In this task, two levers were available and a response on one lever yielded one 45mg food pellet immediately, whereas a response on the other yielded three pellets after an adjusting delay. The delay was initially set at 6s, and it decreased or increased by 1s following responses on the immediate or delayed levers, respectively. A mean adjusted delay (MAD) was calculated upon completion of each daily session, and it served as the quantitative measure of impulsivity. Once MADs stabilized, rats were injected with saline, d-amphetamine (0.5, 1.0, or 2.0mg/kg, s.c.), or methylphenidate (2.5, 5.0, or 10.0mg/kg, s.c.) 15min prior to adjusting delay sessions. EC rats had higher baseline MADs (were less impulsive) than IC rats. Additionally, administration of d-amphetamine, but not methylphenidate, dose-dependently increased impulsive choice (decreased MADs) in EC rats. In IC rats, d-amphetamine and methylphenidate dose-dependently decreased impulsivity (increased MADs). These results indicate that rearing environment influences impulsive choice and moderates the effect of psychostimulants on impulsive choice. Specifically, psychostimulants may decrease environment-dependent impulsive choice in individuals with high levels of impulsivity (e.g., those with ADHD), whereas they may increase impulsive choice in individuals with low levels of impulsivity.     

Behavioral effects of dehydroepiandrosterone in adult male rats

It is well-documented that dehydroepiandrosterone (DHEA) exhibits various behavioral effects in rodents, at least one of which is modulation of learning/memory processes in several test paradigms. However, little is known about the influence of DHEA on cognitive performance in the adult rodents. This work was designed to determine whether chronic DHEA administration during 10 days in the high (0.7 mg/kg, s.c.) or low (0.1 mg/kg, s.c.) doses has any effect on learning/memory abilities and behavior in the adult male rats (5- to 6-month old). Effect of DHEA was estimated in active and passive avoidance tasks, behavior was registered in the elevated "plus" maze and the "open field" test. DHEA in the high dose significantly (p<0.05) increased time spent and the number of enterings in the "open" arms of the elevated "plus" maze in intact male rats as compared with the control rats. DHEA in the low dose significantly (p<0.05) decreased horizontal and vertical locomotor activity and grooming behavior, whereas DHEA in the high dose did not significantly modify behavior in intact rats as compared with control group. Results of the ANOVA on passive avoidance performance revealed no statistically significant differences among the groups receiving DHEA in the high or low doses as compared to the control. However, DHEA in the low dose significantly (p<0.05) reduced the number of correct avoidance responses in intact rats as compared to the control rats, while in rats treated with the high dose DHEA, the active avoidance performance did not differ significantly from the control. Thus, chronic DHEA administration has a modulatory action on the learning and behavior of the adult male rats.     

Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats

This study compared the effects of repeated novel stressors on ‘depressive behaviors’, defined by the forced-swim and open-field tests, in Sprague-Dawley (S-D) and Wistar Kyoto (WKY) rats. Since stress appears to alter brain norepinephrine (NE) activity, this study also investigated the effects of the stressors on β-adrenoceptors (β-ARs),α₂-adrenoceptors (α₂-ARs) and NE transporter (NET) sites in S-D and WKY rats. Stress did not alter¹²⁵I-iodopindolol (¹²⁵I-PIN) binding to β-ARs, nor [³H]idazoxan ([³H]IDAZ) binding toα₂-ARs in S-D rats, compared to non-stressed controls. However, WKY-stressed rats showed a significant reduction in¹²⁵I-IPIN binding to β-ARs in the cortex, hippocampus, amygdala and hypothalamus, and a reduction in [³H]IDAZ binding toα₂-ARs in the amygdala. [³H]nisoxetine ([³H]NIS) binding to NET sites in WKY-stressed rats was also reduced in the cortex, hippocampus and amygdala. When both strains were compared, the most surprising finding was a significantly higher density of NET sites in the hippocampus and amygdala in WKY rats compared to S-D rats. The results of this study indicate that stress, not only exacerbates depressive behavior in WKY rats, but also selectively alters β-ARs,α₂-ARs and NET sites in limbic brain regions. Thus, the WKY strain may serve as a useful animal model for depressive behavior and for the investigation of novel antidepressant drugs.     

Post-weaning environmental enrichment improves BDNF response of adult male rats

The environment could have long lasting effects on the individual phenotype through developmental plasticity. Early environmental enrichment exerts profound biological effects, most of which are quite beneficial ones. To explore the enduring effects of rearing condition quality on BDNF¹ responses, we reared male Wistar rats from weaning to young-adulthood in three different environmental conditions: 1. Enriched 2. Standard, and 3. Isolated. Then, at the age of 16 weeks, 10 rats from each group were randomly chosen and allocated to six common mix cages. They were kept together for 14 weeks. At the end of the experiment, each rat received ten inescapable foot-shocks. Twelve hours later, the BDNF contents of the amygdala and CA1 sub-region of the dorsal hippocampus were measured. The serum BDNF levels, hematocrit values as well as brain and testis weights were also measured. Results showed that the environmental enrichment led to stronger dorsal hippocampal BDNF response and higher serum BDNF levels, while rats from standard laboratory condition showed higher amygdala BDNF response. Also, enriched animals showed higher brain weight compared to isolation reared rats as well as higher testis weight and hematocrit value compared to animals reared in standard laboratory condition. Rats showed less body weights in isolated condition. In conclusion, the BDNF profile of enriched animals might represent the neurobiological correlate of resilience phenotype under a stressful situation.     

Long-lasting and transgenerational effects of an environmental enrichment on memory formation

It has long been believed that genetically determined, but not environmentally acquired, phenotypes can be inherited. However, a large number of recent studies have reported that phenotypes acquired from an animal's environment can be transmitted to the next generation. Moreover, epidemiology studies have hinted that a similar phenomenon occurs in humans. This type of inheritance does not involve gene mutations that change DNA sequence. Instead, it is thought that epigenetic changes in chromatin, such as DNA methylation and histone modification, occur. In this review, we will focus on one exciting new example of this phenomenon, transfer across generations of enhanced synaptic plasticity and memory formation induced by exposure to an "enriched" environment.     

Functional and cellular effects of environmental enrichment after experimental brain infarcts

Our genes interact with environmental stimuli throughout our lives. The attitude and reaction to an acute cerebral trauma or stroke, as well as the pre-lesion life event and activities, can influence functional outcome. Although difficult to separate in adult human beings, genetic and environmental factors can be selectively evaluated in animal studies. Post-ischemic housing in an enriched environment, i.e. larger cages which allow both social interaction and various activities improves functional outcome, modifies gene activation, and increases dendrite branching and number of dendritic spines in pyramidal neurons in layers II-III in the contra-lateral cortex. Furthermore, it alters lesion-induced progenitor cell differentiation and interacts with neocortical transplantation, drug treatment and training. It is proposed that the interaction between environment and specific treatment needs more clinical attention, and that a general stimulating and positive environment is the optimal base for specific interventions in neurological rehabilitation.     

Cage-induced stereotypies, perseveration and the effects of environmental enrichment in laboratory mice

When kept in barren and restrictive cages, animals frequently develop stereotypic behaviour patterns that are characterized by high repetition rates, conspicuous invariance and an apparent lack of function. Although millions of animals are affected, the underlying causes and mechanisms are still unclear. Growing evidence suggests that cage-induced stereotypies may reflect pathological dysfunction within basal ganglia circuitry expressed by perseverative behaviour. In order to assess whether variation in stereotypy performance and variation in perseverative behaviour may have a common cause in ICR CD-1 mice, we assessed the effects of environmental enrichment on both phenomena. We raised 48 female ICR CD-1 mice in standard or enriched cages from three weeks to either 6 or 11 months of age and measured stereotypy level in the home cage and perseveration on an extinction task. We further examined whether enriched rearing conditions (early enrichment) protect mice from the developing stereotypies later in life and whether stereotypies developed in barren cages would persist in an enriched environment (late enrichment) by transferring standard mice to enriched cages and vice versa for 14 weeks after completion of the extinction task. We found no evidence for a causal relation between stereotypy and perseveration in mice. However, transfer to enriched cages reduced stereotypy levels significantly both at 6 and 11 months of age indicating that stereotypies had not become established yet. Finally, we found that removing enrichments at both ages did not induce higher stereotypy levels, thereby confirming earlier reports of a neuroprotective effect of early enrichment.     

Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats

The investigation of methamphetamine exposure during neonatal development in rats has demonstrated that long-term spatial learning deficits are induced. A previous dose-response study showed that administration of 5 mg/kg methamphetamine, four times daily from postnatal days 11 to 20 produced these deficits, although the effects were not as severe as at higher doses of 10 or 15 mg/kg. This study examined concentrations of methamphetamine at or below 5mg/kg given over the same period of time. Five different concentrations of methamphetamine (i.e., 5, 2.5, 1.25, 0.625, or 0) were administered every 2 h four times daily from postnatal days 11 to 20. Body weights, zero maze performance, and Morris water maze learning were examined. A dose-dependent decrease in body weight was observed during the period of methamphetamine administration and these lower weights continued throughout adulthood for the 5, 2.5, and 1.25 mg/kg concentrations, although the adult decreases were negligible. No differences were noted in the zero maze. In the Morris water maze during the acquisition period, dose-dependent differences in spatial orientation were seen, however non-dose related deficits were observed for other parameters. During the shifted platform phase ("reversal"), a similar dose-dependent difference in spatial orientation was observed, although no other effects were noted during this phase. Females performed worse than males regardless of treatment or the phase of learning in the Morris water maze. These data suggest that even lower doses of methamphetamine can alter learning and memory in adulthood, although with less consistent results than with doses higher than 5 mg/kg/dose. These data would caution against even casual use of methamphetamine by women during pregnancy since even low doses could alter the ability of the child to learn.     

Memory in male and female Wistar rats: effects of gonadectomy, and stimulus presentations during the delay interval

The present experiment was designed to investigate the effects of gonadectomy on the response accuracy of male and female Wistar rats in an operant delayed spatial response alternation procedure. Subjects were exposed to 3 randomly presented delay intervals during each experimental session (15, 30 and 60 s). Response accuracy decreased as a function of the duration of the delay interval. Prolonged exposure to the experimental procedure differentially affected the behavior of intact and gonadectomized males and females. Intact males showed a more rapid increase in response accuracy as compared to any of the other groups of subjects, but differences in steady-state behavior were not observed. The effect of stimulus presentations during the delay interval on the alternation accuracy of intact and gonadectomized male and female Wistar rats was studied in a second experimental condition. The presentation of stimuli during the delay interval equally affected response accuracy of intact and gonadectomized subjects at all delay interval durations. Differences between the sexes, or between intact and gonadectomized subjects were not observed in the second experimental condition. The results of the present experiments thus suggest that intact and gonadectomized male and female Wistar rats do not differ with respect to memory as measured in operant delayed spatial alternation tasks, since both males and females were equally susceptible to the presentation of stimuli meant to disrupt ongoing memory processes.