Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress

The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. The modulation of microtubule dynamics depends on the phosphorylation of neuronal microtubule-associated proteins (MAPs). Chronic unpredicted mild stress (CUMS) affects hippocampal structure and function in the rat. The aim of the present work was to investigate the possible alteration of cytoskeleton in the hippocampus of rats exposed to CUMS and re-exposed to CUMS to mimic depression and the recurrence of depression of human. We investigated the effects of CUMS, fluoxetine and re-exposure to CUMS on α-tubulin isoforms associated with microtubule dynamics, MAP-2 and phospho-MAP-2 in the hippocampus of rats. Our results showed that rats submitted to CUMS once showed a significant reduction in locomotion and sucrose preference which indicate a state of anhedonia. These behavioral alterations were accompanied by specific alterations in hippocampal α-tubulin isoforms and phospho-MAP-2 expression, indicating less microtubule dynamics and the possible mechanism. Treatment of fluoxetine could reverse CUMS-induced impairment. Moreover, there were more dramatically changes in behaviors, α-tubulin isoforms and phospho-MAP-2 of rats re-exposed to CUMS compared to the rats exposed to CUMS once. These findings provide evidence that rats exposed to CUMS and re-exposed to CUMS showed impairment of microtubule dynamics accompanied with the decreased level of phospho-MAP-2, providing insight into the role of cytoskeleton in the depression and recurrent of depression.     

Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats

Summary Post-mortem studies have provided evidence for abnormalities of the γ-aminobutyric acid (GABA)-ergic system in schizophrenia. The calcium-binding proteins (CBPs), parvalbumin (PV), calbindin (CB) and calretinin (CR) can be used as markers for specific subpopulations of GABAergic neurons in the brain. Isolation rearing of rats is a non-pharmacological, non-lesion manipulation that leads to deficits in prepulse inhibition of the startle reflex (PPI) and other behavioural and neurochemical alterations reminiscent of schizophrenia. Female rats were reared in social housing (groups of three) or singly for 11 weeks post weaning and PPI was measured. Brains were removed and hippocampal CBP – containing neurons determined following immunocytochemical staining. Compared to socially housed rats, isolated rats exhibited PPI deficits and reductions in PV and CB-immunoreactive cells in the hippocampus, with no significant change in CR. These findings demonstrate selective abnormalities of sub-populations of GABAergic interneurons in the hippocampus of isolation reared rats, which resemble the neuronal deficits seen in this region in schizophrenia.     

Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia.     

Effect of isolation rearing on pre- and post-synaptic serotonergic function in the rat dorsal hippocampus

Several behavioural, neurochemical, and structural alterations found in isolation-reared rats are similar to those in human schizophrenia. This study investigated changes in cholinergic and serotonergic function in the hippocampus following isolation rearing. Rats were reared in social isolation from weaning for 6 weeks before study and compared to group-reared rats. An in vitro electrophysiological study investigated the effect of isolation rearing on postsynaptic 5-HT(1A) function on CA1 hippocampal neurones activated with the muscarinic agonist carbachol and found no change in the sensitivity of these postsynaptic receptors between the groups. However, a change in presynaptic function was identified, as there was a significant reduction in the time taken for neuronal firing to recover to 50% of the original rate following 5-HT (10 microM) application, in isolation compared to group-reared rats. These data suggest a possible change in reuptake following isolation. Uptake studies using (3)[H]5-HT, however, found no change in the inhibition of uptake produced by either fluoxetine or paroxetine in isolation compared to group-reared rats. The selective 5-HT(1B) antagonist CP-294253 (1 microM), increased endogenous 5-HT release from hippocampal slices in vitro and this effect was greater (P < 0.001) in group compared to isolation-reared rats. These results indicate that the change in presynaptic 5-HT neuronal function was due to impaired autoreceptor responsiveness. Carbachol (1 microM) increased the firing rate of all neurones recorded but only a proportion of these showed a concentration-related increase. Isolation rearing increased the sensitivity of neurones, showing a concentration-related increase in firing in response to carbachol, but had no effect on the other neurones. In summary, the present study showed that isolation rearing alters presynaptic 5-HT(1B) but not postsynaptic 5-HT(1A) receptor activity in the hippocampus. Isolation rearing in the rat results in hippocampal dysfunction, including reduced serotonergic and enhanced muscarinic activity of some neurones. These effects may in part underlie the behavioural consequences of isolation relevant to human developmental disorders.     

Fluoxetine administration modulates the cytoskeletal microtubular system in the rat hippocampus

A number of studies suggest that stressful conditions can induce structural alterations in the hippocampus and that antidepressant drugs may prevent such deficits. In particular, the selective serotonin reuptake inhibitor (SSRI) fluoxetine was more effective in modulating different neuronal plasticity phenomena and related molecules in rat hippocampus. Cytoskeletal microtubule dynamics are fundamental to dendrites and axons remodeling, leading to the hypothesis that fluoxetine may affect the microtubular system. However, despite reports of stress‐induced alterations in microtubule dynamics by different stressors, only few studies investigated the in vivo effects of antidepressants on microtubules in specific rat brain regions. The present study investigated the dose‐related (1, 5, or 10 mg/kg i.p.) effects of acute and chronic (21 days) treatments with fluoxetine on the ratio of hippocampal α‐tubulin isoforms which is thought to reflect microtubule dynamics. Western Blot analysis was used to quantify α‐tubulin isoforms, high‐performance liquid chromatography and fluorescence detection was used to measure ex vivo monoamine metabolism. The results showed that acute fluoxetine increased the stable forms acetylated and detyrosinated α‐tubulin. Conversely, chronic fluoxetine decreased acetylated α‐tubulin, indicative of increased microtubule dynamics. The neuron‐specific Δ2‐Tubulin was increased by chronic fluoxetine indicating neuronal involvement in the observed cytoskeletal changes. Although acute and chronic fluoxetine similarly altered serotonin metabolism by inhibition of serotonin reuptake, this showed no apparent correlation to the cytoskeletal perturbations. Our findings demonstrate that fluoxetine administration modulates microtubule dynamics in rat hippocampus. The cytoskeletal effect exerted by fluoxetine may eventually culminate in promoting events of structural neuronal remodeling. Synapse 63:359–364, 2009. © 2009 Wiley‐Liss, Inc.     

Reduced N-acetylaspartate in the temporal cortex of rats reared in isolation.

BACKGROUND: Isolation rearing of rats is a nonpharmacologic, nonlesion manipulation that leads to deficits in prepulse inhibition (PPI) and other behavioral and neurochemical alterations reminiscent of schizophrenia. N-acetylaspartate (NAA) is present in high concentrations in the central nervous system and is found primarily in neurons. N-acetylaspartate is considered to be a marker of both neuronal loss and cellular dysfunction. Magnetic resonance spectroscopy studies have shown reductions of cortical and hippocampal NAA in schizophrenia, and a recent postmortem study has demonstrated a regionally selective temporal cortex deficit. METHODS: The aim of the present study was to determine whether rats reared in isolation exhibit deficits in PPI and reductions in NAA in discrete brain regions, namely the temporal cortex, frontal cortex, hippocampus, and striatum. RESULTS: Compared with socially housed rats, isolation rearing resulted in PPI deficits (p <.05) and reductions in NAA in the temporal cortex (p <.001), with no significant change in the other regions investigated. CONCLUSION: These results suggest a disturbance of neuronal function, reflected by NAA reductions in the temporal cortex in isolation-reared rats, providing further evidence that isolation rearing can mimic aspects of the neuronal pathology of schizophrenia.     

Environmental influence on behaviour and nerve growth factor in the brain

The influence of the environment on the endogenous levels of nerve growth factor (NGF) in the cortex, hippocampus and septum was examined in adult (82 days old) and juvenile (51 days old) rats. Animals were reared/housed for 30 days in an enriched, standard or isolated environment prior to analysis. In addition, another group of rats were given behavioural tests (4 days) after differential rearing/housing before measurements of NGF. We found complex variations in the level of NGF both in juvenile and adult hippocampus after differential environmental rearing/housing. Rearing/housing in an enriched environment improved performance in the Morris maze and decreased spontaneous motor activity. Exposure to behavioural tests caused alterations in adult hippocampus and septum NGF levels. The results show that testing in a novel environment causes small but significant changes in the hippocampal and septal NGF levels depending upon the environmental history of the animal. In view of the purported involvement of the septohippocampal pathway and NGF in the pathophysiology of Alzheimer's disease, our finding suggests that lack of adequate environmental stimulation might be of importance in age-related behavioural and neurochemical deficits.     

Peripubertal viral-like challenge and social isolation mediate overlapping but distinct effects on behaviour and brain interferon regulatory factor 7 expression in the adult Wistar rat

A range of adverse, early life environmental influences such as viral infection and social deprivation are thought to increase risk of psychiatric illness later in life. Here, we used peripheral administration of the viral infection mimic polyriboinosinic-polyribocytidylic acid (polyI:C) to compare the consequences of peripubertal infection and isolation rearing. Isolation rearing induced deficits in sensorimotor gating and recognition memory while no changes in social interaction or spatial learning were observed. PolyI:C injection during the peripubertal period markedly increased expression of interferon-stimulated genes (Ifit2, Prkr, Mx2 and Irf7) in the hippocampal dentate gyrus demonstrating that peripheral administration of the viral mimic in the adolescent animal does have direct effects in the brain. Peripubertal infection mimicry induced a similar but later emerging behavioural deficit in prepulse inhibition implying the existence of a peripubertal window of opportunity for viral-mediated cytokine increases to impact brain development and function. PolyI:C treatment also impaired novel object recognition but did not alter spatial reference memory or social interaction. Combining the polyI:C challenge with social isolation did not exacerbate the behavioural deficits seen with isolation rearing alone. Using Irf7 as a marker, peripubertal viral infection mimicry, isolation rearing and a combination of both were all seen to produce a long-lasting molecular imprint on the interferon-associated signalling pathway in the principal neuron population of the hippocampal dentate gyrus. The data suggest that the sensitivity of brain structure and function to disruption by viral infection extends into the peripubertal period. Moreover, augmented interferon signalling in hippocampus may represent a common molecular imprint of environmental insults associated with neuropsychiatric illnesses like schizophrenia.     

慢性应激及氟西汀治疗后大鼠海马细胞支架的改变

目的 探讨慢性不可预见性应激及氟西汀治疗后大鼠细胞支架微管系统的动态性变化及其可能机制.方法 将24只大鼠按随机数字表法分为对照组(空白对照+生理盐水)、慢性不可预见性温和应激(CUMS)组(CUMS+生理盐水)和氟西汀组(CUMS+氟西汀),每组8只.对大鼠进行连续21 d CUMS后,氟西汀组给予氟西汀(10 mg/kg)治疗21 d,对照组和CUMS组给予生理盐水.实验结束后进行行为学观察,并使用免疫印迹法(western blot)检测大鼠海马乙酰化微管蛋白(Acet-Tub),酪氨酸化微管蛋白(Tyr-Tub),微管结合蛋白2(MAP-2)及磷酸化微管结合蛋白2(phospho-MAP-2).结果 (1)CUMS组糖水偏好[(55.13±11.80)%],总行程[(2736.59±511.20)cm],运动平均速度[(5.69±1.08)cm/s]及直立次数[(2.50±2.00)次]均低于对照组,差异有统计学意义(P＜0.01);氟西汀组上述指标与对照组比较差异无统计学意义(P＞0.05).(2)CUMS组与对照组相比,Acet-Tub表达升高[(171.84±10.34)%],Tyr-Tub[(62.06±9.24)%]和phospho-MAP-2[(68.81±8.93)%]的表达降低,差异有统计学意义(P均＜0.01),MAP-2的表达与对照组比较无统计学意义(P＞0.05);经氟西汀治疗后,Acet-Tub的表达降低为[(96.18±8.92)%],Tyr-Tub和phospho-MAP-2的表达分别升高为[(95.06±8.00)%]、[(100.60±7.30)%],与对照组比较均无统计学意义(P＞0.05).结论 慢性应激后微管动态性减低,神经可塑性受损,氟西汀可以逆转海马的这些损伤,上述过程可能与微管相关蛋白磷酸化水平的变化有关.     

The role of the hippocampus in object recognition in rats: examination of the influence of task parameters and lesion size

Studies examining the effects of hippocampal lesions on object recognition memory in rats have produced conflicting results. The present study investigated how methodological differences and lesion size may have contributed to these discrepancies. In Experiment 1 we compared rats with complete, partial (septal) and sham hippocampal lesions on a spontaneous object recognition task, using a protocol previously reported to result in deficits following large hippocampal lesions . Rats with complete and partial hippocampal lesions were unimpaired, suggesting the hippocampus is not required for object recognition memory. However, rats with partial lesions showed relatively poor performance raising the possibility that floor effects masked a deficit on this group. In Experiment 2, we used a second spontaneous object recognition protocol similar to that used by the two other studies that have reported deficits following hippocampal lesions . Rats with complete hippocampal lesions were significantly impaired, whereas rats with partial lesions were unimpaired. However, the complete lesion group showed less object exploration during the sample phase. Thus, the apparent recognition memory deficit in Experiment 2 may be attributable to differential encoding. Together, these findings suggest that the hippocampus is not required for intact spontaneous object recognition memory. These findings suggest that levels of object exploration during the sample phase may be a critical issue, and raise the possibility that previous reports of object recognition deficits may be due to differences in object exploration rather than deficits in object recognition per se.     

Early rearing environment and dorsal hippocampal ibotenic acid lesions: long-term influences on spatial learning and alternation in the rat

Behavioural responses in a set of spatial and cue tasks were assessed in adult rats that had been given ibotenic acid lesions of the dorsal hippocampus at weaning. The lesions or sham operations were immediately followed by one month of differential rearing, either in enriched, social or isolated housing environments. The differential rearing was followed by standard (social) housing conditions until behavioural testing began at 4 months of age. Compared to sham-operated rats, the rats with early cytotoxic lesions showed substantial impairments on learning and efficient strategy formation in radial arm maze, retention of a spatial location, but not of a cue-marked location, in a + maze and spontaneous alternation. Differential rearing had some long-term effects depending on the task. Sham-operated rats which had been housed in isolation used a pattern of strategies in the radial arm maze that resembled the pattern used by rats with lesions. Early enrichment, on the other hand, alleviated lesion deficits only in a spontaneous alternation task in a T-maze where the variety and salience of proximal cues were maximised. Enrichment increased lesion deficits in the radial maze task, where distal cues only could guide performance. The results suggest that the hippocampus may play an important role in the use of contextual information and that behavioural recovery after early hippocampal damage--limited to situations in which featural information is highly salient--may be permanently induced by rearing in environments, as in enriched ones, where rats can attend to and manipulate environmental cues.     

Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats

The 2-vessel-occlusion + hypotension (2VO + H) model of transient global cerebral ischemia results in neurodegeneration within the CA1 field of the hippocampus, but previous research has failed to demonstrate robust or reliable learning/memory deficits in rats subjected to this treatment. In the present study, sensitive behavioral protocols were developed in an effort to characterize the cognitive impairments following 2VO + H more precisely. Adult rats were exposed to 10 min of bilateral carotid occlusion with simultaneous hypotension. Following recovery, 2VO + H and control rats were subjected to a series of behavioral tests (locomotor activity, sensorimotor battery, water maze [cued, place, learning set], object recognition, and radial arm maze) over an extended recovery period followed by an assessment of neuronal loss in the dorsal hippocampus. The 2VO + H treatment was associated with long-lasting spatial learning deficits in the absence of other behavioral impairments and with neurodegeneration in dorsal hippocampal CA1. Water maze protocols that placed higher memory demands upon the rats (relatively "hard" vs. "easy") were more sensitive for detecting ischemia-induced deficits. We have shown that the use of appropriate behavioral tests (e.g., a relatively difficult place learning task) allowed for the observation of robust spatial learning deficits in a model previously shown to induce relatively subtle behavioral effects. Thus, the 2VO + H model induces both hippocampal neuronal loss and long-term learning deficits in rats, providing a potentially useful model for evaluating therapeutic efficacy.     

Adolescent enrichment partially reverses the social isolation syndrome

Early environmental experience produces profound neural and behavioural effects. For example, animals reared in isolation show increased anxiety, neophobia, and poorer performance in learning and spatial memory tasks. We investigated whether later enrichment reverses some or all of the deficits induced by isolation rearing. Eighty-four male Long-Evans rats (21 days old) were reared under different conditions: enriched (group housed with toys), isolated (one rat/cage), standard (two rats/cage), isolated-enriched, enriched-isolated, isolated-standard, or enriched-standard. In the latter four conditions, animals were housed in the first environment until adolescence (66 days). Following the 90-day rearing period, all animals were assessed in a battery of behavioural tests and cortical thickness was measured postmortem. Isolation rearing led to significant differences in behavioural tests measuring anxiety, spatial learning, and locomotor activity; switching the rearing condition partially reversed these changes. Rearing condition did not affect pain thresholds in the tail flick test or aversive associative learning in the conditioned taste aversion test. Enriched rats had the thickest cortex; isolated rats the thinnest. None of the switch groups differed significantly from standard-reared rats in this measure. Taken together, these results provide novel and interesting information regarding the effects of pre- or post-adolescent enrichment experience on behavioural and neural expression of the social isolation syndrome.     

Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism

Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.     

Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats

Isolation rearing induces various cognitive abnormalities such as reversal learning deficits and reduced prepulse inhibition in rats. However, there are few reports in the literature on its effects on social and emotional functions. In the current study we aimed to address these issues and demonstrated that isolation rearing induced aggression and impaired social recognition, produced moderate anxiogenic effects in the elevated-plus maze, and resulted in hyperactivity in a novel open field. We also found NR2A, NR2B, PSD-95 and SAP-102 mRNA expression were significantly up-regulated in the hippocampus while NR2B was down-regulated in prefrontal cortex in response to isolation rearing. This study advances the use of social isolation as an animal model for studying etiological mechanisms of various neuropsychiatric disorders.     

Hippocampal cytotoxic lesion effects on species-typical behaviours in mice

The behavioural effects of hippocampal lesions have been extensively documented in rats. However, paradigms developed for rats cannot be assumed to transfer straightforwardly to mice; the behaviour of the two species differs in many respects. Mice are currently the species of choice for targeted genetic manipulations. A number of these programs aim to modulate hippocampal function. The present studies were therefore designed to provide a behavioural profile of selective, cytotoxic hippocampal lesions in tasks appropriate for mice. The lesions abolished food hoarding from a source outside the home base, and reduced the tendency to displace food pellets from a tube inside the home cage (burrowing). Lesioned mice showed reductions of directed exploration (rearing and head dipping), but not locomotor activity, in a holeboard and open field, and explored the edges of their home cages less when the lids were removed. Nest construction was also impaired. These effects were not due to gross motor impairments, as formal tests revealed no deficiencies in co-ordination or strength. There were suggestions of changes in emotionality, although a more consistent finding was that lesioned mice were often slower to initiate behaviour in novel surroundings, which may be congruent with the other deficits we observed. These results may aid interpretation of the many genetic manipulations that target the hippocampus, and of neurodegenerative conditions that induce hippocampal pathology.     

慢性不可预见性温和应激后大鼠行为及海马细胞支架的改变

目的研究慢性不可预见性温和应激所致的动物行为学改变及细胞支架微管系统的动态性改变。方法将大鼠随机分为应激模型组（8只,以下简称模型组）和对照组（8只）,对模型组大鼠进行连续21d的慢性不可预见性应激。进行行为学观察,使用western blotting检测乙酰化微管蛋白（Acet—Tub）,酪氨酸微管蛋白（Tyr—Tub）。结果（1）模型组大鼠慢性应激后糖水偏好及自主活动显著减低,与对照组有显著差异;（2）模型组大鼠慢性应激后海马Acet—Tub表达升高,Tyr—Tub表达减低,与对照组有显著差异。结论慢性应激后微管动态性减低,神经可塑性受损。     

Protective effect of Hsp70i against chronic social isolation stress in the rat hippocampus

Stress-related glucocorticoids and glutamate release has been implicated in depression. Glutamate neurotoxicity is mediated, in part, by the production of nitric oxide via nitric oxide synthase (NOS) isoforms and mitochondrial damage. We previously reported that chronic social isolation stress triggers proapoptotic signaling in the rat prefrontal cortex, but not in the hippocampus. Given that the hippocampus is highly sensitive to stress, we examined signaling cascades underlying the hippocampal cellular protection through the NOS pathway, antioxidant capacity and heat shock protein (Hsp) expression. We investigated neuronal (nNOS) and inducible (iNOS) protein levels, subcellular protein distributions of nuclear factor-κB (NF-κB), CuZnSOD and MnSOD activity, reduced glutathione (GSH), stress-inducible Hsp70 (Hsp70i) protein expression and serum corticosterone (CORT) levels of rats exposed to 21 days of chronic social isolation, an animal model of depression, alone or in combination with 2 h of acute immobilization or cold stress (combined stress). Both acute stressors elevated CORT, with lesser magnitude increase in chronically isolated rats exposed to novel acute stress as compared to acute stressors alone, indicating compromised HPA axis activity. Acute cold decreased nuclear CuZnSOD activity and stimulated NF-κB nuclear translocation. Chronic social isolation resulted in no activation of NF-κB, but led to decreased GSH, iNOS and increased nNOS and Hsp70i levels, alterations that remained following combined stressors. Decreased mitochondrial MnSOD activity after combined stressors suggests compromised detoxifying capacity. These data indicate that Hsp70i upregulation may provide hippocampal cellular protection against chronic social isolation stress mediated by downregulation of iNOS protein expression through suppression of NF-κB activation.     

Rat neonatal immune challenge alters adult responses to cerebral ischaemia.

Infection, inflammation, and hyperthermia associated with cerebral ischaemia are known to contribute to enhanced neuronal cell loss and more severe behavioural deficits. Because neonatal exposure to an immune challenge has been shown to alter the severity of inflammatory and febrile responses to a further immune challenge experienced in adulthood, we hypothesised that this could also alter temperature responses and neuronal survival after ischaemia. Thus, male Sprague-Dawley rats were treated at postnatal day 14 with a single injection of the bacterial endotoxin lipopolysaccharide (LPS) and were examined as adults for temperature changes, behavioural deficits, and neuronal cell loss associated with global cerebral ischaemia after a two-vessel occlusion (2VO). Neonatally LPS-treated rats showed behavioural differences in a novel object exploration paradigm, as well as altered temperature responses to the 2VO compared with neonatally saline-treated controls. Interestingly, these neonatally LPS-treated rats also showed increased cell loss in the central nucleus of the amygdala, a region that is important in the processing of emotional responses, but that is not usually examined in animal models of cerebral ischaemia. No differences were seen in the CA1, CA3, or dentate gyrus regions of the hippocampus. This work shows the importance of examining brain regions other than the hippocampus in association with global ischaemia. We also highlight the importance of the early period of development in programming an animal's ability to deal with injury such as cerebral ischaemia in adulthood.     

Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins,microtubule‐associated protein 2, and synapsin I

Brain oxytocin regulates a variety of social and affiliative behaviors and affects also learning and memory. However, mechanisms of its action at the level of neuronal circuits are not fully understood. The present study tests the hypothesis that molecular factors required for memory formation and synaptic plasticity, including brain‐derived neurotrophic factor, neural growth factor, nestin, microtubule‐associated protein 2 (MAP2), and synapsin I, are enhanced by central administration of oxytocin. We also investigated whether oxytocin enhances object recognition and acts as anxiolytic agent. Therefore, male Wistar rats were infused continuously with oxytocin (20 ng/µl) via an osmotic minipump into the lateral cerebral ventricle for 7 days; controls were infused with vehicle. The object recognition test, open field test, and elevated plus maze test were performed on the sixth, seventh, and eighth days from starting the infusion. No significant effects of oxytocin on anxious‐like behavior were observed. The object recognition test showed that oxytocin‐treated rats significantly preferred unknown objects. Oxytocin treatment significantly increased gene expression and protein levels of neurotrophins, MAP2, and synapsin I in the hippocampus. No changes were observed in nestin expression. Our results provide the first direct evidence implicating oxytocin as a regulator of brain plasticity at the level of changes of neuronal growth factors, cytoskeletal proteins, and behavior. The data support assumption that oxytocin is important for short‐term hippocampus‐dependent memory. © 2015 Wiley Periodicals, Inc.