Hippocampus Of Adult Male Rats Research Articles

Activity-Dependent Synaptic Plasticity in the Medial Prefrontal Cortex of Male Rats Underlies Resilience-Related Behaviors to Social Adversity.

Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.

The effect of Brucella abortus on glial activation and cell death in adult male rat's hippocampus

A zoonotic disease called brucellosis can cause flu-like symptoms and heart inflammation. The bacteria responsible for this disease can also enter the brain, causing a condition called neurobrucellosis that can result in long-term neurological problems. In this study, researchers aimed to determine the changes in the hippocampal cells of rats infected with Brucella. For the study, 24 adult male albino rats were inoculated with 1 × 106 CFU Brucella abortus 544. The rats were then deeply anesthetized, and their hippocampus samples were taken for stereological, histological, and molecular studies. The results showed that the infected rats had increased microgliosis and astrogliosis. Furthermore, a high level of caspase-3 in their hippocampal tissue indicated their susceptibility to apoptosis. Additionally, there was a decrease in expression of Ki67, which further supported this. Sholl's analysis confirmed a significant failure in glial morphology. The study demonstrated that the pathogen has the ability to destroy the hippocampus and potentially affect its normal physiology. However, more research is needed to clarify various aspects of neurobrucellosis.

Vitamin C Alleviates Neurobehavioral Deficits, IGF1 Expression, and Neuronal Damage Induced by Chronic Social Isolation Stress in the Hippocampus of Adult Male Rats

Vitamin C Alleviates Neurobehavioral Deficits, IGF1 Expression, and Neuronal Damage Induced by Chronic Social Isolation Stress in the Hippocampus of Adult Male Rats

Conditioned morphine tolerance promotes neurogenesis, dendritic remodelling and pro-plasticity molecules in the adult rat hippocampus.

Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned- and conditioned-morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion-specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac-1 and RhoA mRNA levels as pro-plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro-plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine-tolerance plasticity in the hippocampus.

3-acetylpyridine induced behavioral dysfunction and neuronal loss in the striatum and hippocampus of adult male rats

3-acetylpyridine (3-AP) is a neurotoxin that is known to mainly affect the inferior olivary nucleus (ION) in the brain stem. Although several studies have explored the effect of this neurotoxin, still further investigation is required to understand the impact of this toxin on different parts of the brain. In this research, two groups of rats were studied, the 3-AP-treated and the control groups. Behavioral, stereological, and immunohistochemical analyses were performed. The locomotor activity of the 3-AP-treated rats decreased whereas their anxiety levels were higher than in normal controls. Also, memory performance was impaired in animals in the 3-AP group. Microscopic observations showed a decline in the numerical density of neurons in the hippocampus and striatum along with gliosis. Although this toxin is used to affect the ION, it exerts a neurotoxic effect on different brain regions.

Mechanism of Microglial Cell Activation in the Benzophenone-3 Exposure Model.

Benzophenone-3 (BP-3) is the most commonly used UV filter in cosmetics, which is absorbed through the skin and crosses the blood-brain barrier. This compound increases extracellular glutamate concentrations, lipid peroxidation, the number of microglia cells and induces process of apoptosis. The aim of this study was to determine the effect of BP-3 on the activation and polarization of microglial cells in the frontal cortex and hippocampus of adult male rats exposed to BP-3 prenatally and then for two weeks in adulthood. It has been found, that exposure to BP-3 reduced the expression of the marker of the M2 phenotype of glial cells in both examined brain structures. An increase in the CD86/CD206 microglial phenotype ratio, expression of transcription factor NFκB and activity of caspase-1 were observed only in the frontal cortex, whereas BP-3 increased the level of glucocorticoid receptors in the hippocampus. The in vitro study conducted in the primary culture of rat frontal cortical microglia cells showed that BP-3 increased the LPS-stimulated release of pro-inflammatory cytokines IL-1α, IL-1β, TNFα, but in cultures without LPS there was decreased IL-1α, IL-6 and TNFα production, while the IL-18 and IP-10 was elevated. The obtained results indicate that differences in the level of immunoactivation between the frontal cortex and the hippocampus may result from the action of this compound on glucocorticoid receptors. In turn, changes in cytokine production in microglial cells indicate that BP-3 aggravates the LPS-induced immunoactivation.

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1-21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (1HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals.

Acute adolescent morphine exposure improves dark avoidance memory and enhances long-term potentiation of ventral hippocampal CA1 during adulthood in rats.

Adolescence represents a distinctive vulnerable period when exposure to stressful situations including opioid exposure can entail lasting effects on brain and can change neural mechanisms involved in memory formation for drug-associated cues, possibly increasing vulnerability of adolescents to addiction. Herein, the effects of acute adolescent morphine exposure (AAME, two injections of 2.5mg/kg SC morphine on PND 31) were therefore investigated 6 weeks later (adulthood) on avoidance memory and hippocampal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in transvers slices from the ventral hippocampus in adult male rats using field recordings technique. Animal body weight was measured from PND 31 throughout PND 40 and also in four time points with 1 week intervals from adolescence to adulthood (PNDs 48, 55, 62 and 69) to evaluate the effect of AAME on the weight gain. We showed that there were no effects on body weight, anxiety-like behaviour and locomotor activity, even until adulthood. There was an improved dark avoidance memory during adulthood. Finally, AAME had no effects on baseline synaptic responses and resulted in a decrease in the mean values of the field excitatory postsynaptic potential slopes required to evoke the half-maximal population spike amplitude and an enhancement of LTP magnitude (%) in the ventral CA1 during adulthood. Briefly, our results suggest long-lasting effects of acute adolescent morphine exposure on the ventral hippocampus, which begin the enhancing of synaptic plasticity and the improving of emotional memory in adulthood.

A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral-CA1, temporoammonic-CA1, and perforant pathway-dentate gyrus synapses along the longitudinal axis of the hippocampus.

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABAA subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABAA subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis.

Study of the Combined Effect of Low Frequency Stimulation and Carbamazepine on Motor and Balance Behavior Indices during Unilateral Kindling in the CA1 Region of the Dorsal Hippocampus in Adult Male Rats

Study of the Combined Effect of Low Frequency Stimulation and Carbamazepine on Motor and Balance Behavior Indices during Unilateral Kindling in the CA1 Region of the Dorsal Hippocampus in Adult Male Rats

Chronic exposure to methadone impairs memory, induces microgliosis, astrogliosis and neuroinflammation in the hippocampus of adult male rats

Methadone is a centrally-acting synthetic opioid analgesic widely used in methadone maintenance therapy (MMT) programs throughout the world. Given its neurotoxic effects, particularly on the hippocampus, this study aims to address the behavioral and histological alterations in the hippocampus associated with methadone administration. To do so, twenty-four adult male albino rats were randomized into two groups, methadone treatment and control. Methadone was administered subcutaneously (2.5–10 mg/kg) once a day for two consecutive weeks. A comparison was drawn with behavioral and structural changes recorded in the control group. The results showed that methadone administration interrupted spatial learning and memory function. Accordingly, treating rats with methadone not only induced cell death but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. Furthermore, the results demonstrated that treating rats with methadone decreased the complexity of astrocyte processes and the complexity of microglia processes. These findings suggest that methadone altered the special distribution of neurons. Also, a substantial increase was observed in the expression of TNF-α due to methadone. According to the findings, methadone administration exerts a neurodegenerative effect on the hippocampus via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Evaluation of the effect of nicotine and O-acetyl-L-carnitine on testosterone-induced spatial learning impairment in Morris water maze and assessment of protein markers

The hippocampus has an essential role in learning and memory and is a target for androgen actions. Thus, the effect of testosterone and its metabolites on learning and memory has attracted researchers' attention.The present study aimed to identify the effects of four-day bilateral intra-hippocampal infusion of nicotine and o-Acetyl L-carnitine alone and in combination on testosterone enanthate (TE)-induced spatial learning deficits using Morris water maze (MWM). The expression of CREB, pCREB and BDNF proteins was quantified using western blots.We observed that bilateral intra-hippocampal infusion of TE significantly impaired spatial learning and a significant decrease in CREB, pCREB and BDNF protein markers compared to a control group that did not receive TE. In addition, administration of O-acetyl L-carnitine and/or nicotine reversed TE-induced spatial learning impairment in behavioural and molecular assessments.Thus, our findings suggest that administration of TE in the hippocampus of adult male rats impairs memory function, possibly via down-regulation of cAMP/PKA-CREB-BDNF signaling pathway.

Anti-inflammatory, Antioxidant, and Antiapoptotic Action of Metformin Attenuates Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders.

Fetal alcohol exposure has permanent effects on the brain structure, leading to functional deficits in several aspects of behavior, including learning and memory. Alcohol-induced neurocognitive impairment in offsprings is included with activation of oxidative- inflammatory cascade followed with wide apoptotic neurodegeneration in several brain areas, such as the hippocampus. Metformin is the first-line treatment for diabetic patients. It rapidly crosses the blood-brain barrier (BBB) and exerts antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we evaluated the protective effects of metformin on ethanol-related neuroinflammation, as well as neuron apoptosis in the hippocampus of adult male rat in animal model of fetal alcohol spectrum disorders. Treatment with ethanol in milk solution (5.25 and 27.8g/kg, respectively) was conducted by intragastric intubation at 2-10days after birth. To examine the antioxidant and anti-inflammatory properties of metformin, an ELISA assay was performed for determining the tumor necrosis factor-α (TNF-α) and antioxidant enzyme concentrations. Immunohistochemical staining was conducted for evaluating the glial fibrillary acidic protein (GFAP) and cleaved caspase-3 expression. Based on the results, metformin caused a significant increase in the superoxide dismutase (SOD) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.01) activities. On the other hand, it reduced the concentrations of TNF-α and malondialdehyde, compared to the ethanol group (P < 0.01). In the metformin group, there was a reduction in cell apoptosis in the hippocampus, as well as GFAP-positive cells (P < 0.01). Overall, apoptotic signaling, regulated by the oxidative inflammatory cascade, can be suppressed by metformin in adult brain rats following animal model of fetal alcohol spectrum disorders.

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.

Methamphetamine augments HIV-1 gp120 inhibition of synaptic transmission and plasticity in rat hippocampal slices: Implications for methamphetamine exacerbation of HIV-associated neurocognitive disorders

Methamphetamine (Meth) abuse and human immunodeficiency virus type 1 (HIV-1) infection are two major public health problems worldwide. Being frequently comorbid with HIV-1 infection, Meth abuse exacerbates neurocognitive impairment in HIV-1-infected individuals even in the era of combined antiretroviral therapy. While a large body of research have studied the individual effects of Meth and HIV-1 envelope glycoprotein 120 (gp120) in the brain, far less has focused on their synergistic influence. Moreover, it is well-documented that the hippocampus is the primary site of spatial learning and long-term memory formation. Dysregulation of activity-dependent synaptic transmission and plasticity in the hippocampus is believed to impair neurocognitive function. To uncover the underlying mechanisms for increased incidence and severity of HIV-1-associated neurocognitive disorders (HAND) in HIV-1-infected patients with Meth abuse, we investigated acute individual and combined effects of Meth (20 μM) and gp120 (200 pM) on synaptic transmission and plasticity in the CA1 region of young adult male rat hippocampus, a brain region known to be vulnerable to HIV-1 infection. Our results showed that acute localized application of Meth and gp120 each alone onto the CA1 region reduced short-term dynamics of input-output responses and frequency facilitation, and attenuated long-term potentiation (LTP) induced by either high frequency stimulation or theta burst stimulation. A synergistic augmentation on activity-dependent synaptic plasticity was observed when Meth and gp120 were applied in combination. Paired-pulse facilitation results exhibited an altered facilitation ratio, suggesting a presynaptic site of action. Further studies revealed an involvement of microglia NLRP3 inflammasome activation in Meth augmentation of gp120-mediated attenuation of LTP. Taken together, our results demonstrated Meth augmented gp120 attenuation of LTP in the hippocampus. Since LTP is the accepted experimental analog of learning at the synaptic level, such augmentation may underlie Meth exacerbation of HAND observed clinically.

Study of Anticonvulsant Effects of Carbamazepine During Epileptic Process by Unilateral Kindling of CA1 Dorsal Hippocampus in Adult Male Rats

Study of Anticonvulsant Effects of Carbamazepine During Epileptic Process by Unilateral Kindling of CA1 Dorsal Hippocampus in Adult Male Rats

Memantine improves memory and hippocampal proliferation in adult male rats.

Neurogenesis occurs during the embryological development of the brain. However, it is universally accepted that in all adult mammalian brains, there are two sites of high-density cell division: the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation. Doxorubicin (DOX) is an anthracycline agent which results in cognitive deterioration and memory impairment, whereas memantine (MEM) is an NMDA receptor antagonist which is approved for the treatment of Alzheimer's dementia. Many studies have revealed MEM's positive impact on memory and demonstrated that it stimulates neuronal division in the hippocampus. This study aimed to assess the effect of MEM on spatial memory and neural proliferation in the hippocampus in adult male rats treated with DOX. For this purpose, forty male Sprague-Dawley rats were divided into four groups of ten rats each according to the agent: control, MEM (2.5 mg/kg), DOX (2 mg/kg), and DOX with MEM. The rats were given seven intraperitoneal injections every other day. We tracked the rat's weights to assess the weight-reducing effects of the drugs. In order to test spatial memory, the rats were subjected to the novel location recognition (NLR) task 30 minutes after the last injection. Additionally, Ki67 immunohistochemistry was performed to examine hippocampal proliferation. The results showed a significant reduction in discrimination index (DI) in the DOX-treated group compared to MEM- (p < 0.001) and MEM with DOX-treated groups (p < 0.001). There was a significant increase in Ki67-positive cells in the MEM-treated group compared to the saline-treated group. Treatment with DOX impaired hippocampal proliferation compared to treatment with MEM or saline. The co-administration of MEM with DOX ameliorated the decline in hippocampal proliferation compared to treatment with DOX alone. There was a significant weight reduction in the DOX group in comparison to the control group, but MEM attenuated DOX-induced weight loss. Rats treated with DOX displayed a drop in memory, hippocampal proliferation, and weight compared to the MEM-treated group, whereas the co-administration of MEM with DOX protected memory, hippocampal proliferation, and doxorubicin-induced weight loss.

Gene Therapy Vector Encoding Neuropeptide Y and Its Receptor Y2 for Future Treatment of Epilepsy: Preclinical Data in Rats.

Gene therapy to treat pharmacoresistant temporal lobe epilepsy in humans is now being developed using an AAV vector (CG01) that encodes the combination of neuropeptide Y and its antiepileptic receptor Y2. With this in mind, the present study aimed to provide important preclinical data on the effects of CG01 on the duration of transgene expression, cellular tropism, and potential side effects on body weight and cognitive function. The CG01 vector was administered unilaterally into the dorsal and ventral hippocampus of adult male rats and expression of both transgenes was found to remain elevated without a sign of decline at 6 months post-injection. CG01 appeared to mediate expression selectively in hippocampal neurons, without expression in astrocytes or oligodendrocytes. No effects were seen on body weight as well as on short- or long-term memory as revealed by testing in the Y-maze or Morris water maze tests. Thus these data show that unilateral CG01 vector treatment as future gene therapy in pharmacoresistant temporal lobe epilepsy patients should result in stable and long-term expression predominantly in neurons and be well tolerated without side effects on body weight and cognitive function.

Voluntary wheel running promotes improvements in biomarkers associated with neurogenic activity in adult male rats

In rodents, hippocampal neurogenesis and synaptogenesis phenomena are affected by exercise. However, the role of exercise parameters such as intensity, duration, and mode on molecular mechanisms involved in these processes has not been elucidated. In this study, we evaluated the effects of different intensities and modes of running on the expression of genes contributing to neuronal differentiation and synapse formation in the hippocampus of adult male rats. Adult male Wistar rats (n = 24) were randomly divided into control, low-intensity running (LIR), high-intensity running (HIR), and the voluntary wheel running (WR) conditions. Changes in the expression of microRNA-124 (miR-124), microRNA-132 (miR-132), and their respective targets, were analyzed using quantitative RT-PCR and Western blotting techniques. Our results showed that WR compared to treadmill running increased miR-124 and miR-132 expression, while reducing the expression of their respective targets, glucocorticoid receptor (GR), SRY-Box 9 (SOX9), and GTP-activated protein P250 (P250GAP). Differences in expression levels were statistically significant (ps < 0.05), except for the expression of GR in HIR (P = 0.09). Moreover, the expression level of gene coding for the transcription factor cAMP-response element binding protein (CREB) was significantly higher in the WR group compared to the treadmill running groups (P = 0.001). Western blotting techniques indicated that the level of the CREB protein was higher in WR compared to the other groups qualitatively. These findings demonstrated a more dramatic effect for voluntary running on biomarkers that are associated with stimulating neurogenesis and synapse formation in the hippocampus of male rats compared with forced treadmill running. In addition, greater positive effects were observed for lower-intensity treadmill running as compared with high-intensity running.

Atomoxetine improves hippocampal cell proliferation but not memory in Doxorubicin-treated adult male rats.

Atomoxetine (ATX) is a noradrenaline reuptake inhibitor used to treat Attention deficit hyperactive disorder (ADHD), or improve cognition in normal subjects. Cancer patients treated with systemic adjuvant chemotherapy have described experiencing deterioration in cognition. Doxorubicin (DOX, Adriamycin) is one of the anthracycline families used in chemotherapy, which has a deteriorating effect on both cognition and proliferation. The cognitive effects of ATX require inputs from the hippocampus. The aim of this study was to examine spatial memory and proliferation in the subgranular zone (SGZ) of the DG in adult Lister Hooded rats treated either alone or with a combination of Atomoxetine (30 mg kg−1 day−1, six i.p. doses, one injection every other day) and Doxorubicin (DOX) ( 2 mg kg−1 day−1, six i.p. doses, one injection every other day). Spatial memory was tested using the Novel location recognition (NLR) test, and proliferation of hippocampal cells was quantified using immunohistochemistry for the proliferative marker Ki67. Results showed that ATX treatment has improved the NLR task and increased cell proliferation in the SGZ of the DG, compared with saline‐treated controls. Animals treated with DOX only showed deficits in NLR task, and co‐administration of ATX along with DOX did not improve their performance. DOX chemotherapy caused a significant reduction in the number of proliferating cells in the SGZ of the DG compared with saline‐treated controls. This reduction was reversed by co‐administration of ATX. The above findings suggest that DOX can negatively affect both cell proliferation and memory and ATX co‐administration improves proliferation, but not memory in the adult male rat hippocampus.