Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

Background

Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.

Methods

TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg^-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.

Results

At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.

Conclusion

These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.     

Social threat and novel cage stress-induced sustained extracellular-regulated kinase1/2 (ERK1/2) phosphorylation but differential modulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus of NMRI mice

The extracellular signal-regulated kinase1/2 (ERK1/2) pathway has a key role in cell survival and brain plasticity, processes that are impaired following exposure to stressful situations. We have recently validated two repeated intermittent stress procedures in male NMRI mice, social threat and repeated exposure to a novel cage, which result in clear behavioral effects following 4 weeks of application. The present results demonstrate that both repeated intermittent stress procedures alter the activity of the ERK1/2 pathway in the brain, as shown by changes in phosphorylated ERK1/2 (phospho-ERK1/2) protein expression and in the expression of downstream proteins: phosphorylated cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF), in the hippocampus, the frontal cortex and the hypothalamus. The hippocampus showed greater responsiveness to stress as the two stressors increased phospho-ERK1/2 and BDNF expression under acute condition. Following repeated stress, hyperphosphorylation of ERK1/2 was associated with up-regulation of hippocampal BDNF expression in the social threat group but not in mice exposed to novel cage. This lack of a pro-survival effect of ERK1/2 with repeated novel cage exposure may constitute an early event in stress-mediated brain pathology. The sustained BDNF up-regulation in the hippocampi of mice subjected to repeated social threat could be related to rewarding aspects of aggressive interactions, suggested by our previous studies.     

Central noradrenergic depletion by DSP-4 prevents stress-induced memory impairments in the object recognition task

Environmental stress produces adverse affects on memory in humans and rodents. Increased noradrenergic neurotransmission is a major component of the response to stress and noradrenaline (NA) plays an important role in modulating processes involved in learning and memory. The present study investigated the effect of NA depletion on stress-induced changes on memory performance in the mouse. Central NA depletion was induced using the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) and verified by high performance liquid chromatography (HPLC). A novel cage stress procedure involving exposure to a new clean cage for 1 h per day, 4 days per week for 4 weeks, was used to produce stress-induced memory deficits measured using the object recognition task. 50 mg/kg DSP-4 produced large and sustained reductions in NA levels in the frontal cortex and hippocampus measured 24 h, 1 week and 5 weeks after treatment. Four weeks of exposure to novel cage stress induced a memory deficit in the object recognition task which was prevented by DSP-4 pre-treatment (50 mg/kg 1 week before the commencement of stress).These findings indicate that chronic environmental stress adversely affects recognition memory and that this effect is, in part, mediated by the noradrenergic stress response. The implication of these findings is that drugs targeting the noradrenergic system to reduce over-activity may be beneficial in the treatment of stress-related mental disorders such as post-traumatic stress disorder or anxiety in which memory is affected.     

Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice

The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.     

Long-term effects of the periadolescent environment on exploratory activity and aggressive behaviour in mice: social versus physical enrichment

The aims of the present study were (i) to investigate the effects of environmental enrichment during periadolescence on different behavioural and neurochemical responses in male CD-1 mice at adulthood and (ii) to describe the relative role of the physical and social components of the enrichment in producing these effects. Thirty 5-day-old mice were randomly assigned to one of the following housing conditions lasting five consecutive days: (i) individually housed in a standard cage, (ii) housed in pairs in a standard cage, (iii) individually housed in a physically enriched cage, and (iv) housed in pairs in a physically enriched cage. At adulthood, 80 days after the enrichment exposure, the explorative behaviour in an open field, as well as the behaviour in agonistic encounters, was evaluated in association with the analysis of selected central (hypothalamic levels of nerve growth factor (NGF) and brain-derived growth factor(BDNF)) and peripheral (plasma corticosterone levels) biochemical parameters. The results show that the long-term effects of the physical and the social enrichment are different and not additive. In particular, while social enrichment by itself exerted very limited effects, physical enrichment decreased the exploratory activity and altered social behaviour. Mice housed in pairs in an enriched cage showed low activity levels in the open field, and they tended to become more frequently dominant, although showing a more affiliative and less aggressive social interaction strategy. Furthermore, they presented low levels of hypothalamic NGF and high levels of brain-derived growth factor, suggesting an important effect of the combination of social and physical enrichment on neurobehavioral markers of brain plasticity and on animal ability to cope with social challenges.     

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice

Increased accumulation of amyloid-beta peptide (Aβ) and neuroinflammation is known to exist within the Alzheimer's disease (AD) brain. However, it remains unclear which form of Aβ pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aβ level, rather than amyloid plaque burden or insoluble Aβ level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aβ species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.     

Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice

Environmental enrichment (EE) has been largely used to investigate behavioral modifications and neuroplasticity in the adult brain both in normal and pathological conditions. The interaction between individual behavioral traits with EE responsiveness has not been investigated within the same strain. By using two extremes of CF1 mice that differ by their exploratory behavior in the Open Field (OF) task (Kazlauckas V, 2005), denominated as Low (LE) and High (HE) Exploratory Mice, the present study evaluated if EE during adulthood could modify the putative differences between LE and HE mice on exploratory behavior, memory performance and hippocampal BDNF levels. To this end, we investigated the effect of adult LE and HE mice after 2 months of enriched or standard housing conditions on the open field, on novel object recognition, on the inhibitory avoidance task and on hippocampal BDNF immunocontent. LE showed low exploratory behavior, less retention in the inhibitory avoidance and lower hippocampal BDNF levels. EE enhanced exploratory behavior, memory performance and hippocampal BDNF levels both in LE and HE mice. Importantly, the general profile of LE mice submitted to EE was similar to HE mice housed in standard conditions. These results show that internalized behavior of LE mice can be significantly modified by exposure to an enriched environment even during adulthood. These observations may contribute to investigate biological mechanisms and therapeutical interventions for individuals with internalized psychiatric disorders.     

Adrenocortical and behavioural response to chronic restraint stress in neurokinin-1 receptor knockout mice

Brain substance P and its receptor (neurokinin-1, NK1) have a widespread brain distribution and are involved in an important number of behavioural and physiological responses to emotional stimuli. However, the role of NK1 receptors in the consequences of exposure to chronic stress has not been explored. The present study focused on the role of these receptors in the hypothalamic-pituitary-adrenal (HPA) response to daily repeated restraint stress (evaluated by plasma corticosterone levels), as well as on the effect of this procedure on anxiety-like behaviour, spatial learning and memory in the Morris water maze (MWM), a hippocampus-dependent task. Adult null mutant NK1-/- mice, with a C57BL/6J background, and the corresponding wild-type mice showed similar resting corticosterone levels and, also, did not differ in corticosterone response to a first restraint. Nevertheless, adaptation to the repeated stressor was faster in NK1-/- mice. Chronic restraint modestly increased anxiety-like behaviour in the light-dark test, irrespective of genotype. Throughout the days of the MWM trials, NK1-/- mice showed a similar learning rate to that of wild-type mice, but had lower levels of thigmotaxis and showed a better retention in the probe trial. Chronic restraint stress did not affect these variables in either genotype. These results indicate that deletion of the NK1 receptor does not alter behavioural susceptibility to chronic repeated stress in mice, but accelerates adaptation of the HPA axis. In addition, deletion may result in lower levels of thigmotaxis and improved short-term spatial memory, perhaps reflecting a better learning strategy in the MWM.     

Synaptic transmission is impaired prior to plaque formation in amyloid precursor protein–overexpressing mice without altering behaviorally-correlated sharp wave–ripple complexes

One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques in brains of affected patients. Several recent studies provided evidence that soluble oligomer forms of amyloid-β (Aβ) rather than plaques determine cognitive decline. In vitro studies using artificial Aβ oligomer preparations suggest that such pathophysiology is caused by a specific impairment of synaptic function. We examined whether synaptic deficits occur before deposition of insoluble fibrillar Aβ by analyzing brain slices taken from young Tg2576 mice overexpressing mutant amyloid precursor protein. Excitatory synaptic transmission in the hippocampal CA1 region was strongly impaired before plaque development, suggesting a dissociation of an early synaptic impairment, probably caused by soluble oligomeric amyloid-β, from subsequent plaque formation. At higher age neurotransmission was also decreased in wild type mice, paralleling a cognitive decline of normal aged animals. Memory formation in rats is accompanied by distinct hippocampal network oscillations. It has recently been shown that hippocampal gamma oscillations, a network correlate of exploratory behavior, are impaired in amyloid precursor protein (APP)–overexpressing mice. We determined whether sharp wave–ripple complexes, which contribute to memory consolidation during slow wave-sleep, are modified in Tg2576 mice. Interestingly, neither sharp waves nor superimposed ripples were changed at pre-plaque or plaque stages. During aging, however, there was a strong reduction of sharp wave frequency and ripple energy in wild type and APP-overexpressing animals. This indicates that the reported changes in network oscillations following APP-overexpression are specific for gamma oscillations, whereas aging has a more general effect on network properties. Taken together our data suggest that non-fibrillar forms of Aβ—possibly Aβ oligomers—specifically interfere with synaptic function in Tg2576, but do not globally alter memory-related network properties. We propose that mechanisms leading to Aβ-related cognitive decline are different from those related to aging.     

Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease

Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease.     

Habituation to the test cage influences amphetamine-induced locomotion and Fos expression and increases FosB/DeltaFosB-like immunoreactivity in mice

Pre-exposure to the testing cage (habituation or familiarization) is a common procedure aimed at reducing the interference of novelty-induced arousal and drug-independent individual differences on neural and behavioral measures. However, recent results suggest that this procedure might exert a major influence on the effects of addictive drugs. The present experiments tested the effects of repeated exposure to a test cage (1 h daily for four consecutive days) on amphetamine-induced locomotion and Fos expression as well as on FosB/DeltaFosB-like immunoreactivity in mice of the C57BL/6J and DBA/2J inbred strains that differ for the response to amphetamine, stress and novelty. Daily experiences with the test cage increased FosB/DeltaFosB-like immunoreactivity in the medial-prefrontal cortex of both strains of mice and in the caudate of mice of the C57 strain, as reported for repeated stress in the rat. Moreover, previous habituation to the test cage reduced the locomotor response to a low dose of amphetamine only in DBA mice while it reduced amphetamine-induced Fos expression in medial-prefrontal cortex, dorsal caudate and the accumbens shell of mice of the C57 strain. These results demonstrate indexes of stress-like plasticity in the brains of mice exposed to a procedure of familiarization to the testing environment. Moreover, they suggest that the procedure of daily familiarization influences the pattern of brain Fos expression induced by amphetamine. Finally, they indicate complex interactions between experience with the testing environment, genotype and drug.     

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.     

Stress-induced impairment of inhibitory avoidance learning in female neuromedin B receptor-deficient mice

Neuromedin B (NMB) is a mammalian bombesin (BN)-like peptide that exerts its function via the neuromedin B receptor (NMB-R). The NMB/NMB-R system is involved in stress response, and therefore we examined behavioral properties in female mice lacking NMB-R using a restraint-induced stress paradigm. Thirty minutes of restraint in a wire mesh cage constituted a sufficient stress stimulus for mice as evidenced by elevated blood glucose concentrations in stressed wild-type and NMB-R-deficient mice. Using a one-trial passive avoidance test, stressed NMB-R-deficient mice exhibited a marked reduction in memory performance. NMB-R-deficient mice exhibited elevated spontaneous activity in a novel environment compared to non-stressed mutant mice after 30-min stress, and a similar difference was also observed between stressed/non-stressed wild-type mice. An elevated plus maze test showed that the stress stimulus had no effect on anxiety in either wild-type or NMB-R-deficient mice. Furthermore, pain response of wild-type and NMB-R-deficient mice induced by electric foot shock was not affected under either stressed or non-stressed conditions. These results indicate that impaired memory performance in stressed NMB-R-deficient mice is not a consequence of changes in spontaneous activity, anxiety, or pain response, and suggest that the NMB/NMB-R pathway may play a role in regulating the stress response via the neural system that controls learning and memory.     

Olfactory bulbectomy in mice induces alterations in exploratory behavior

The olfactory bulbectomy syndrome is thought to represent a rodent model for psychomotor agitated depression. While this model has been extensively characterized in rats, fewer studies have been conducted with mice. Therefore, the present study aimed at extending the characterization of the OBX-induced behavioral syndrome in mice, using tests like open field, novel object exploration, novel cage and T-maze learning. OBX mice exhibited hyperactivity in a brightly illuminated open field, and also in a novel home cage as well as in the T-maze. Furthermore, OBX mice demonstrated increased exploratory behavior in the novel object test and in the T-maze. The complex alterations described here with respect to locomotion and exploration are robust and can be achieved by relatively simple test procedures. The extended behavioral characterization of the murine OBX model may contribute in particular to the increasing need to test transgenic mice for the presence of depression-like behaviors.     

Effects of Mild Early Life Stress on Abnormal Emotion-related Behaviors in 5-HTT Knockout Mice

A low-expressing polymorphic variant of the serotonin transporter (5-HTT) gene has been associated with emotional disorders in humans and non-human primates following exposure to early life trauma. 5-HTT gene knockout (KO) mice exhibit increased anxiety- and depression-related behaviors, and provide a model to study interactions between 5-HTT gene variation and early life stress. The present study assessed the effects of postnatal footshock stress on the development of emotion-related behaviors in 5-HTT KO mice. Results showed that 5-HTT KO mice displayed a profile of suppressed exploratory behavior and increased anxiety-like behavior in the light/dark, elevated plus-maze and open field tests, as well as increased depression-related behavior in the forced swim test following repeated exposure to the test. Postnatal exposure to footshock stress did not affect emotion-related behaviors in non-mutant C57BL/6J mice or modify phenotypic abnormalities in 5-HTT KO. Data provide further evidence of emotional abnormalities following genetic disruption of the 5-HTT. Edited by Gene Fisch     

Glucocorticoid metabolites in rabbit faeces--influence of environmental enrichment and cage size

The concentration of glucocorticoid metabolites (GCM) in rabbit faeces has been suggested as a non-invasive indicator of stress. In the present study, GCM concentrations were measured in faeces of fattening rabbits kept in groups of eight, at seven different stocking densities (between 5 and 20 animals/m²), with or without environmental enrichment (a wooden structure used mainly for gnawing and resting). Transport (30 min) was used as an acute novel stressor to assess the glucocorticoid response to stress under the different housing conditions. GCM concentrations were elevated post-transport (P < 0.001). Whilst cage size had no influence on GCM, enrichment reduced GCM concentrations before as well as after transport (P = 0.007 in both cases). Effects of cage size and enrichment on growth characteristics were negligible, whilst enrichment decreased cage manipulation and social contact. The results indicate that even short transport durations may be stressful for rabbits, and that enrichment may decrease housing stress. They suggest that measuring baseline GCM concentrations in faeces is a useful tool to evaluate chronic stress in rabbits, whilst measuring the response to a novel stressor did not provide additional insight.     

Sensitization of the plasma corticosterone response to novel environments

In Experiment 1, ICR Swiss mice were exposed to one of two novel cages for 1, 6, or 10 30-min trials. Plasma corticosterone elevations were greater in the more novel than in the less novel cage and following the sixth as compared to the first and tenth exposures. In Experiment 2, BALB/c and C57BL/6J mice and Sprague-Dawley rats also exhibited significant, though modest, increases in corticosterone levels from their first to their sixth 30-min exposures to the more novel cage. These findings demonstrate generalization of an apparent sensitization of the plasma corticosterone response across the two levels of novelty and four strains of laboratory rodents tested here. The transience of the effect may explain some earlier inconsistencies in the literature. In Experiment 3, five daily 30-min exposures to the more novel environment minimally raised resting corticosterone levels of ICR Swiss mice. Further, corticosterone levels during a first exposure were no greater at 15 or 45 min than at 30 min. These results suggest that the increase in corticosterone with repeated exposures reflects a true sensitization of the corticosterone response rather than an increase in resting levels with repeated exposures or a shift in the time course of the corticosterone response.     

Short exposures to enriched environments can increase genetic variability of behavior in mice.

Previous work indicates that mice of different genotypes reared in enriched environments show differential increases in performance on a food-seeking task. In this study 2 experiments examined the effects in selected mice strains of short exposures to such enrichment. Experiment 1 indicated that 48 hr of exposure to enriched cages was sufficient to produce results found previously when subjects were reared from birth in enriched cages. Experiment 2 indicated that as little as 6 hr of exposure to an enriched cage was sufficient to produce almost maximal enrichment effects in C57BL/10J mice.     

Impaired "episodic-like" object memory in adult APPswe transgenic mice

An early clinical symptom of Alzheimer's disease is impaired episodic memory. However, the precise pathological event(s) that underpins this deficit remains unclear. In the present study, the authors examined whether wild-type mice and Tg2576 mice expressing an amyloid precursor protein (APP) mutation are able to form an integrated memory of the spatio-temporal context in which objects are presented. In Experiment 1, wild-type mice, but not Tg2576 mice that were 10-12 months old, explored objects presented in a novel location. In Experiment 2, wild-type mice explored an object that was presented both earlier in a sequence and in a different location relative to other objects that possessed only one of these properties (i.e., memory for "what," "where," and "when" items were presented). In contrast, the behavior of adult Tg2576 mice was influenced only by the temporal order in which objects were presented. These results demonstrate that wild-type, but not APP-mutant, mice are able to form an "episodic-like" memory of the spatio-temporal properties of objects and support the hypothesis that aberrant APP processing contributes to impairments in event memory.     

Neonatal novelty exposure, dynamics of brain asymmetry, and social recognition memory

Brief and transient early-life stimulation via neonatal handling and neonatal novelty exposure can lead to differential changes within the right and left brains. In rats, these lateralized changes have been demonstrated behaviorally, neuroanatomically, and neurophysiologically. Recently, we found that neonatal novelty exposure can prolong the duration of social recognition memory from less than 2 hr to at least 24 hr among male rats reared in social isolation and that this enhancement is associated with an initial right-turn preference in a novel testing cage. In contrast to stable forms of asymmetry, such as handedness, we show that this turning asymmetry is dynamic-decreasing as the animal adjusts to the novel testing environment over a 2-day period. This change in turning asymmetry was found only among animals that experienced neonatal novelty exposure during the first 3 weeks of their lives. Furthermore, individual differences in short-term social recognition memory for a conspecific can be predicted by this change in functional asymmetry.