Levels Of Hippocampal Neurogenesis Research Articles

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway

BackgroundRadiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood.MethodsRIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus.ResultsrTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1β were upregulated.ConclusionOur study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

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.

Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis.

Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience. This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies. Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training. Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility. These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.

Alterations in hippocampal neurogenesis and hippocampal insulin signaling pathway in rat with metabolic syndrome.

We aimed to examine the level of hippocampal neurogenesis, and assess learning and anxiety and the level of some proteins involving insulin signaling pathways in rats with Metabolic Syndrome (MetS); and to reveal the relationship among them. Totally, 30 Wistar-albino rats were used. The rats were divided into three groups: Control, MetS, and MetS+Ins. Immunohistochemical staining was performed to evaluate the levels of neurogenesis markers; Doublecortin (DCX), Neuronal-Differentiation-1 (NeuroD1), Ki67, and Neuronal nuclear protein (NeuN). Then, cleaved caspase-3 and TUNEL labeling were performed to detect the level of apoptosis. Additionally, behavior tests were performed to evaluate the learning-memory levels and anxiety-like behaviors. Insulin, Insulin Receptor (IR), Insulin Receptor Substrate (IRS2), glucose transporter (GLUT)-3, and GLUT4 protein expression levels were analyzed to evaluate the possible changes in the insulin signaling pathway. An increase in anxiety with memory deficiency was observed in MetS. In the hippocampus of MetS, an increase was detected in the level of apoptosis, whereas a decrease was detected in the expression level of the neurogenesis marker. Insulin secretion and IR levels decreased in hippocampal neurons. We observed that GLUT3 and GLUT4 levels increased because of the non-activated insulin signaling pathway. We think that the insulin signaling pathway may have an effect on the decreased neurogenesis in the MetS group. So, the evaluation of the Mitogen-activated protein kinase (MAPK) pathway and the investigation of the effect of endoplasmic reticulum stress on this pathway will be among the targets of our future studies.

Sex differences in inflammation in the hippocampus and amygdala across the lifespan in rats: associations with cognitive bias

BackgroundCognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias in rats that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of male and female rats across the lifespan.ResultsAfter cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Adolescent male rats had higher hippocampal neurogenesis than adolescent females after cognitive bias testing and young rats that underwent cognitive bias testing had higher levels of hippocampal neurogenesis than controls. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males.ConclusionsOverall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.

Caffeic Acid Alleviates Memory and Hippocampal Neurogenesis Deficits in Aging Rats Induced by D-Galactose

Hippocampal neurogenesis occurs throughout life, but it declines with age. D-galactose (D-gal) enhances cellular senescence through oxidative stress leading to neurodegeneration and memory impairment. Caffeic acid (CA) acts as an antioxidant via decreasing brain oxidative stress. This study aims to investigate the advantages of CA in alleviating the loss of memory and neurogenesis production in the hippocampus in aged rats activated by D-gal. Fifty-four male Sprague-Dawley rats were unpredictably arranged into six groups. In the D-gal group, rats were administered D-gal (50 mg/kg) by intraperitoneal (i.p.) injection. For the CA groups, rats received 20 or 40 mg/kg CA by oral gavage. In the co-treated groups, rats received D-gal (50 mg/kg) and CA (20 or 40 mg/kg) for eight weeks. The results of novel object location (NOL) and novel object recognition (NOR) tests showed memory deficits. Moreover, a decline of neurogenesis in the hippocampus was detected in rats that received D-gal by detecting rat endothelial cell antigen-1 (RECA-1)/Ki-67, 5-bromo-2′-deoxyuridine (BrdU)/neuronal nuclear protein (NeuN), doublecortin (DCX) by means of staining to evaluate blood vessel associated proliferating cells, neuronal cell survival and premature neurons, respectively. By contrast, CA attenuated these effects. Our results postulate that CA attenuated the impairment of memory in D-gal-stimulated aging by up-regulating levels of hippocampal neurogenesis.

Hippocampal neurogenesis interferes with extinction and reinstatement of methamphetamine-associated reward memory in mice

Drugs of abuse, including morphine and cocaine, can reduce hippocampal neurogenesis (HN). Whereas promotion of HN is being increasingly recognized as a promising strategy for treating morphine and cocaine addiction. The present study is focused on exploring the changes of HN during methamphetamine (METH) administration and further clarify if HN is involved in METH-associated reward memory. After successfully establishing the conditioned place preference (CPP) paradigm to simulate the METH-associated reward memory in C57BL/6 mice, we observed that HN was significantly inhibited during METH (2 mg/kg, i. p.) administration and returned to normal after the extinction of METH CPP, as indicated by the immunostaining of bromodeoxyuridine (BrdU) and doublecortin (DCX) in the hippocampus. To promote/inhibit HN levels, 7,8-dihydroxyflavone (DHF), a small tyrosine kinase receptor B (TrkB) agonist and temozolomide (TMZ), an alkylating agent, were administered intraperitoneally (i.p.), respectively. The data showed that either DHF (5 mg/kg, i. p.) or TMZ (25 mg/kg, i. p.) pre-treatment before METH administration could significantly prolong extinction and enhance reinstatement of the reward memory. Notably, DHF treatment after METH administration significantly facilitated extinction and inhibited METH reinstatement, while TMZ treatment resulted in opposite effects. The present study indicated that METH administration could induce a temporal inhibitory effect on HN. More importantly, promotion of HN after the acquisition of METH-associated reward memory, but not inhibition of HN or promotion of HN before the acquisition of reward memory, could facilitate METH extinction and inhibit METH reinstatement, indicating the beneficial effect of HN on METH addiction by erasing the according reward memory.

Inflammation increases the development of depression behaviors in male rats after spinal cord injury

Following spinal cord injury, 18–26% of patients are diagnosed with depressive disorders, compared to 8–12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9–10, 19–20, and 29–30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.

Chronic Jet Lag Simulation Decreases Hippocampal Neurogenesis and Enhances Depressive Behaviors and Cognitive Deficits in Adult Male Rats.

There is a long history that protracted periods of circadian disruption, such as through frequent transmeridian travel or rotating shift work, can have a significant impact on brain function and health. In addition, several studies have shown that chronic periods of circadian misalignment can be a significant risk factor for the development of depression and anxiety in some individuals with a history of psychiatric illness. In animal models, circadian disruption can be introduced through either phase advances or delays in the light–dark cycle. However, the impact of chronic phase shifts on affective behavior in rats has not been well-studied. In the present study, male rats were subjected to either weekly 6 h phase advances (e.g., traveling eastbound from New York to Paris) or 6 h phase delays (e.g., traveling westbound from New York to Hawaii) in their light/dark cycle for 8 weeks. The effect of chronic phase shifts was then examined on a range of emotional and cognitive behaviors. We found that rats exposed to frequent phase advances, which mirror conditions of chronic jet lag in humans, exhibited impairments in object recognition memory and showed signature symptoms of depression, including anhedonia, increased anxiety behavior, and higher levels of immobility in the forced swim test. In addition, rats housed on the phase advance schedule also had lower levels of hippocampal neurogenesis and immature neurons showed reduced dendritic complexity compared to controls. These behavioral and neurogenic changes were direction-specific and were not observed after frequent phase delays. Taken together, these findings support the view that circadian disruption through chronic jet lag exposure can suppress hippocampal neurogenesis, which can have a significant impact on memory and mood-related behaviors.

Isolating the key factors defining the magnitude of hippocampal neurogenesis’ effects on anxiety, memory and pattern separation

In this paper, I analyze the hypothesis that hippocampal neurogenesis (HN) exerts its effects on behavior via activation of inhibitory circuits in the hippocampus. Using a very simple mathematical model (half-borrowed from biochemistry) to aid the reasoning, I show that the key factors determining the magnitude of HN's effects on behavior are: the baseline levels of HN in the animal, the efficiency of the animal's inhibitory circuits, the strength/intensity of the stimulus presented to the animal and how much accuracy the behavioral task requires from the information contained in the hippocampal representations. Taken together, those factors can help explain patterns observed in the behavioral results for memory, pattern separation and anxiety. The conclusions of the analysis suggest that HN's effects on inhibitory circuits can explain the impact of neurogenesis on both emotion and cognition and provide a framework to interpret future studies about the effects of HN on different behaviors, with animals of different ages and of different species.

Folic acid, but not folate, regulates different stages of neurogenesis in the ventral hippocampus of adult female rats.

Folate is an important regulator of hippocampal neurogenesis, and folic acid is needed prenatally to reduce the risk of neural tube defects. Both high levels of folic acid and low levels of folate can be harmful to health because low levels of folate have been linked to several diseases while high folic acid supplements can mask a vitamin B12 deficiency. Depressed patients exhibit folate deficiencies, lower levels of hippocampal neurogenesis, elevated levels of homocysteine and elevated levels of the stress hormone, cortisol, which may be inter-related. In the present study, we were interested in whether different doses of natural folate or synthetic folic acid diets can influence neurogenesis in the hippocampus, levels of plasma homocysteine and serum corticosterone in adult female rats. Adult female Sprague-Dawley rats underwent dietary interventions for 29days. Animals were randomly assigned to six different dietary groups: folate deficient+succinylsulphathiazole (SST), low 5-methyltetrahydrofolate (5-MTHF), low 5-MTHF+(SST), high 5-MTHF+SST, low folic acid and high folic acid. SST was added to a subset of the 5-MTHF diets to eliminate folic acid production in the gut. Before and after dietary treatment, blood samples were collected for corticosterone and homocysteine analysis, and brain tissue was collected for neurogenesis analysis. High folic acid and low 5-MTHF without SST increased the number of immature neurones (doublecortin-expressing cells) within the ventral hippocampus compared to folate deficient controls. Low 5-MTHF without SST significantly increased the number of immature neurones compared to low and high 5-MTHF+SST, indicating that SST interfered with elevations in neurogenesis. Low folic acid and high 5-MTHF+SST reduced plasma homocysteine levels compared to controls, although there was no significant effect of diet on serum corticosterone levels. In addition,low folic acid and high 5-MTHF+SST reduced the number of mature new neurones in the ventral hippocampus (bromodeoxyuridine/NeuN-positive cells) compared to folate deficient controls. Overall, folic acid dose-dependently influenced neurogenesis with low levels decreasing but high levels increasing neurogenesis in the ventral hippocampus, suggesting that this region, which is important for regulating stress, is particularly sensitive to folic acid in diets. Furthermore, the addition of SST negated the effects of 5-MTHF to increase neurogenesis in the ventral hippocampus.

Recovery of “Lost” Infant Memories in Mice

Hippocampus-dependent, event-related memories formed in early infancy in human and non-human animals are rapidly forgotten. Recently we found that high levels of hippocampal neurogenesis contribute to accelerated rates of forgetting during infancy. Here, we ask whether these memories formed in infancy are permanently erased (i.e., storage failure) or become progressively inaccessible with time (i.e., retrieval failure). To do this, we developed an optogenetic strategy that allowed us to permanently express channelrhodopsin-2 (ChR2) in neuronal ensembles that were activated during contextual fear encoding in infant mice. We then asked whether reactivation of ChR2-tagged ensembles in the dentate gyrus was sufficient for memory recovery in adulthood. We found that optogenetic stimulation of tagged dentate gyrus neurons recovered "lost" infant memories up to 3months following training and that memory recovery was associated with broader reactivation of tagged hippocampal and cortical neuronal ensembles.

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.SIGNIFICANCE STATEMENT New neurons are generated in the hippocampus throughout life. As they integrate into the hippocampus, they remodel neural circuitry, potentially making information stored in those circuits harder to access. Consistent with this, increasing hippocampal neurogenesis after learning induces forgetting of the learnt information. The current study in mice asks whether these forgetting effects depend on the age of the memory. We found that post-training increases in hippocampal neurogenesis only impacted recently acquired, and not remotely acquired, hippocampal memories. These experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting, and suggest remote memories are less sensitive to changes in hippocampal neurogenesis levels because they no longer depend critically on the hippocampus for their expression.

Inter-individual variation in genes governing human hippocampal progenitor differentiation in vitro is associated with hippocampal volume in adulthood

Hippocampal volumes are smaller in psychiatric disorder patients and lower levels of hippocampal neurogenesis are the hypothesized cause. Understanding which molecular processes regulate hippocampal progenitor differentiation might aid in the identification of novel drug targets that can promote larger hippocampal volumes. Here we use a unique human cell line to assay genome-wide expression changes when hippocampal progenitor cells differentiate. RNA was extracted from proliferating cells versus differentiated neural cells and applied to Illumina Human HT-12 v4 Expression BeadChips. Linear regressions were used to determine the effect of differentiation on probe expression and we assessed enrichment for gene ontology (GO) terms. Genetic pathway analysis (MAGMA) was used to evaluate the relationship between hippocampal progenitor cell differentiation and adult hippocampal volume, using results from the imaging genomics consortium, ENIGMA. Downregulated transcripts were enriched for mitotic processes and upregulated transcripts were enriched for cell differentiation. Upregulated (differentiation) transcripts specifically, were also predictive of adult hippocampal volume; with Early growth response protein 2 identified as a hub transcription factor within the top GO term, and a potential drug target. Our results suggest that genes governing differentiation, rather than mitosis, have an impact on adult hippocampal volume and that these genes represent important drug targets.

Neurobiological Mechanisms of Chemotherapy-induced Cognitive Impairment in a Transgenic Model of Breast Cancer

Animal studies have reinforced clinical reports of cognitive impairment in cancer survivors following chemotherapy but, until now, all pre-clinical research in this area has been conducted on normal rodents. The present study investigated the effects of chemotherapy on cognition and underlying biological mechanisms in the FVB/N-Tg (MMTV-neu) 202 Mul/J mouse, a well-characterized transgenic model of breast cancer that has similarities to the tumorigenesis which occurs in humans. Tumor-bearing and control mice received three weekly injections of a combination of methotrexate + 5-fluorouracil, or an equal volume of saline. Different aspects of learning and memory were measured before and after treatment. The effects of tumor and chemotherapy on neurogenesis, neuro-inflammatory cytokine activity, and brain volume, as they relate to corresponding cognitive changes, were also measured. The toxic effects of chemotherapy extended to the cancerous model in which substantial cognitive impairment was also associated with the disease. Cognitive deficits were greatest in tumorigenic mice that received the anti-cancer drugs. Both tumor growth and chemotherapy caused significant changes in brain volume, including the hippocampus and frontal lobes, two structures that are directly implicated in cognitive tasks that were shown to be vulnerable. The level of hippocampal neurogenesis in adulthood was suppressed in chemotherapy-treated mice and associated with loss of hippocampus-controlled cognitive function. Dysregulation of cytokine activity was found in tumorigenic mice and associated with impaired cognitive performance. The results show that chemotherapy and tumor development independently contribute to cognitive deficits through different biological mechanisms.

Comparison of Adult Hippocampal Neurogenesis and Susceptibility to Treadmill Exercise in Nine Mouse Strains.

The genetic background of mice has various influences on the efficacy of physical exercise, as well as adult neurogenesis in the hippocampus. In this study, we investigated the basal level of hippocampal neurogenesis, as well as the effects of treadmill exercise on adult hippocampal neurogenesis in 9 mouse strains: 8 very commonly used laboratory inbred mouse strains (C57BL/6, BALB/c, A/J, C3H/HeJ, DBA/1, DBA/2, 129/SvJ, and FVB) and 1 outbred mouse strain (ICR). All 9 strains showed diverse basal levels of cell proliferation, neuroblast differentiation, and integration into granule cells in the sedentary group. C57BL/6 mice showed the highest levels of cell proliferation, neuroblast differentiation, and integration into granule cells at basal levels, and the DBA/2 mice showed the lowest levels. The efficacy of integration into granule cells was maximal in ICR mice. Treadmill exercise increased adult hippocampal neurogenesis in all 9 mouse strains. These results suggest that the genetic background of mice affects hippocampal neurogenesis and C57BL/6 mice are the most useful strain to assess basal levels of cell proliferation and neuroblast differentiation, but not maturation into granule cells. In addition, the DBA/2 strain is not suitable for studying hippocampal neurogenesis.

Switching Adolescent High-Fat Diet to Adult Control Diet Restores Neurocognitive Alterations.

In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence in adolescents is particularly alarming since this is a period of ongoing maturation for brain structures (including the hippocampus and amygdala) and for the hypothalamic-pituitary-adrenal (HPA) stress axis, which is required for cognitive and emotional processing. We recently demonstrated that adolescent, but not adult, high-fat diet (HF) exposure leads to impaired hippocampal function and enhanced amygdala function through HPA axis alteration (Boitard et al., 2012, 2014, 2015). Here, we assessed whether the effects of adolescent HF consumption on brain function are permanent or reversible. After adolescent exposure to HF, switching to a standard control diet restored levels of hippocampal neurogenesis and normalized enhanced HPA axis reactivity, amygdala activity and avoidance memory. Therefore, while the adolescent period is highly vulnerable to the deleterious effects of diet-induced obesity, adult exposure to a standard diet appears sufficient to reverse alterations of brain function.

Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms.

New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus, and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimer's disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimer's disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimer's disease. Lastly, we discuss the detectability of neurogenesis in the live mouse and human brain, as well as the therapeutic implications of enhancing neurogenesis for the treatment of cognitive deficits and Alzheimer's disease.

Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus.

Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2’-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis.

Neurogenesis-mediated forgetting minimizes proactive interference

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting.