Changes In Hippocampal Neurogenesis Research Articles

Depression-like behavior is associated with deficits in cognition and hippocampal neurogenesis in a subset of spinally contused male, but not female, rats

Depression and cognitive deficits present at higher rates among people with spinal cord injury (SCI) compared to the general population, yet these SCI comorbidities are poorly addressed. Sex and age appear to play roles in depression incidence, but consensus on the direction of their effects is limited. Systemic and cortical inflammation and disruptions in hippocampal neurogenesis have been identified as potential treatment targets, but a comprehensive understanding of these mechanisms remains elusive.We used a rodent SCI model to interrogate these gaps in knowledge. We examined post-injury depression-like behavior and cognitive deficits, as well as the association between affect, cognition, chronic hippocampal inflammation and hippocampal neurogenesis, in young and middle-aged male and female Sprague-Dawley rats. Depression-like behavior manifested in male and female subsets of SCI rats irrespective of age, at rates commensurate with the incidence of clinical depression. Changes in components of behavior were driven by sex and age, and affective outcomes were independent of common post-injury pathophysiological outcomes including locomotor functional deficits and spinal lesion severity. Interestingly, however, only male depression-like SCI rats exhibited deficits in hippocampal-associated spatial cognition. Neurogenesis was also disrupted in only SCI males in regions of the hippocampus responsible for affective outcomes. Decreased neurogenesis among middle-aged male subjects coincided with increases in numbers of the pro-inflammatory markers CD86 and iNOS, while middle-aged females had increased numbers of cells expressing Iba-1 and anti-inflammatory marker CD206.Overall, the present data suggest that post-SCI depression and cognition may be affected, in part, by sex- and age-dependent changes in hippocampal neurogenesis and inflammation. Hippocampal neurogenesis is a potential target to address psychological wellbeing after SCI, but therapeutic strategies must carefully consider sex and age as biological variables.

Sleep deprivation in adolescent mice impairs long-term memory till early adulthood via suppression of hippocampal astrocytes.

Sleep deficiency is a rampant issue in modern society, serving as a pathogenic element contributing to learning and memory impairment, with heightened sensitivity observed in children. Clinical observations suggest that learning disabilities associated with insufficient sleep during adolescence can persist through adulthood, but experimental evidence for this is lacking. In this study, we examined the impact of early-life sleep deprivation (SD) on both short-term and long-term memory, tracking the effects sequentially into adulthood. We employed a modified multiple-platform method mouse model to investigate these outcomes. SD induced over a 14-day period, beginning on postnatal day 28 (PND28) in mice, led to significant impairment in long-term memory (while short-term memory remained unaffected) at PND42. Notably, this dysfunction persisted into adulthood at PND85. The specific impairment observed in long-term memory was elucidated through histopathological alterations in hippocampal neurogenesis, as evidenced by bromodeoxyuridine (BrdU) signals, observed both at PND42 and PND85. Furthermore, the hippocampal region exhibited significantly diminished protein expressions of astrocytes, characterized by lowered levels of aquaporin 4 (AQP4), a representative molecule involved in brain clearance processes, and reduced protein expressions of brain-derived neurotrophic factors. In conclusion, we have presented experimental evidence indicating that sleep deficiency-related impairment of long-term memory in adolescence can endure into adulthood. The corresponding mechanisms may indicate that the modification of astrocyte-related molecules has led to changes in hippocampal neurogenesis.

Memory loss and aberrant neurogenesis in mice exposed to patient anti-N-methyl-d-aspartate receptor antibodies

ObjectiveAnti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis. MethodsMonoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8–12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3–4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2–12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout. ResultsMice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9–11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3–4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8–10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation. SignificanceThese findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.

Caffeic acid protects against l-methionine induced reduction in neurogenesis and cognitive impairment in a rat model

l-methionine (L-met) is a substantial non-polar amino acid for normal development. L-met is converted to homocysteine that leads to hyperhomocysteinemia and subsequent excessive homocysteine in serum resulting in stimulating oxidative stress and vascular dementia. Several studies have found that hyperhomocysteine causes neuronal cell damage, which leads to memory impairment. Caffeic acid is a substrate in phenolic compound discovered in plant biosynthesis. Caffeic acid contains biological antioxidant and neuroprotective properties. The neuroprotective reaction of caffeic acid can protect against the brain disruption from hydrogen peroxide produced by oxidative stress. It also enhances GSH and superoxide dismutase activities, which protect against neuron cell loss caused by oxidative stress in the hippocampus. Hence, we investigated the protective role of caffeic acid in hippocampal neurogenesis and cognitive impairment induced by L-met in rats. Six groups of Sprague Dawley rats were assigned including control, L-met (1.7 g/kg/day), caffeic acid (20, 40 mg/kg), and L-met + caffeic acid (20, 40 mg/kg) groups. Spatial and recognition memories were subsequently examined using novel object location (NOL) and novel object recognition (NOR) tests. Moreover, the immunofluorescence technique was performed to detect Ki-67/RECA-1, bromodeoxyuridine (BrdU)/NeuN and p21 markers to represent hippocampal neurogenesis changes. The results revealed decreases in vasculature related cell proliferation and neuronal cell survival. By contrast, cell cycle arrest was increased in the L-met group. These results showed the association of the spatial and recognition memory impairments. However, the deterioration can be restored by co-administration with caffeic acid.

Effect of a New Substance with Pyridoindole Structure on Adult Neurogenesis, Shape of Neurons, and Behavioral Outcomes in a Chronic Mild Stress Model in Rats.

Despite an accumulating number of studies, treatments for depression are currently insufficient. Therefore, the search for new substances with antidepressant potential is very important. In this study, we hypothesized that treatment with a newly synthesized pyridoindole derivative compound SMe1EC2M3 would result in protective and antidepressant-like effects on behavioral outcomes and reverse the impaired adult hippocampal neurogenesis caused by chronic mild stress (CMS). We found that chronic administration of 5 mg/kg and 25 mg/kg SMe1EC2M3 to adult Sprague Dawley rats ameliorated the consequences of CMS on immobility and swimming time in a forced swim test. A slight sedative effect of the highest dose of SMe1EC2M3 in the nonstress group was observed in the open field. SMe1EC2M3 in the highest dose ameliorated CMS-induced decreases in the sucrose preference test. Administration of SMe1EC2M3 significantly increased SOX2-positive cells in the hippocampal dentate gyrus (DG) in CMS compared to control animals. A significant reduction in glial fibrillary acid protein (GFAP)-positive cells in the DG of CMS compared to control animals was observed. Administration of both 5 and 25 mg/kg SMe1EC2M3 significantly increased signal of GFAP-positive cells in the DG of CMS animals. No such effects of SMe1EC2M3 were observed in the cornu ammonis hippocampal area. Additionally, we found that incubation of primary hippocampal neurons in the presence of 1.50 µM SMe1EC2M3 significantly stimulated the length of neurites. Overall, we found that the negative effects of CMS on depression-like behavior are partially reduced by the administration of SMe1EC2M3 and are associated with changes in hippocampal neurogenesis and neuronal differentiation. SMe1EC2M3 represents a potential drug candidate with positive neuroplastic effects and neurogenesis-associated effects in therapeutic approaches to depression.

Comparing the antidepressant-like effects of electroconvulsive seizures in adolescent and adult female rats: an intensity dose–response study

BackgroundThe induction of electroconvulsive seizures (ECS) in rodents induces sex- and age-specific disparities in antidepressant-like responses, with females and young age being the most unresponsive ones. Since the electrical charge needed to induce an effective convulsion is also altered by these variables, our aim was to compare different dose-intensities of ECS exclusively in female rats, since there is a lack of preclinical data characterizing this particular sex, while also evaluating efficacy during distinctive age periods of treatment (adolescence vs. adulthood).MethodsAdolescent and adult female Sprague–Dawley rats were exposed to an intensity dose–response study (55, 75 or 95 mA; 0.6 s, 100 Hz, 1 session/day, 5 days). The particular characteristics of the induced convulsions (tonic, clonic, recovery times) were monitored during treatment. Antidepressant-like responses were evaluated under the stress of the forced-swim test 1-, 3-, and 7-days post-treatment (i.e., improved immobility time as an indicative of an antidepressant-like response), and brains were collected 24 h later (8 days post-treatment) to evaluate potential changes in hippocampal neurogenesis (Ki-67 and NeuroD) by immunohistochemistry.ResultsThe lowest intensities tested of ECS (55 and 75 mA) induced an antidepressant-like effect in adult female rats, but rendered insufficient in adolescence. The lack of efficacy observed in adolescent rats paralleled differences in the characteristics of the seizures induced by ECS as compared to adulthood. In line with prior results, different dose-intensities of ECS modulated hippocampal neurogenesis in a comparable fashion with age (i.e., increased survival of neural progenitors 8 days post-treatment).ConclusionsIn conjunction, these results reinforce the importance of fine-tuning the parameters of ECS that might render efficacious while considering sex and age as essential variables for treatment response, and suggest that other molecular mechanisms, beside the partial role of hippocampal neurogenesis, might be participating in the antidepressant-like effects induced by ECS.

Decreased Hippocampal Neurogenesis in Aged Male Wistar Rats Is Not Associated with Memory Acquisition in a Water Maze.

Brain aging is associated with a progressive decrease in learning abilities, memory, attention, decision making, and sensory perception. Age-related cognitive disturbances may be related to a decrease in the functional capacities of the hippocampus. This brain region is essential for learning and memory, and the lifelong neurogenesis occurring in the subgranular zone of the dentate gyrus may be a key event mediating the mnemonic functions of the hippocampus. In the present study, we investigated whether age-related changes in hippocampal neurogenesis are associated with learning and memory disturbances. Four- and 24-month-old rats were trained to find a hidden platform in a water maze. Though the older group showed higher latency to search the platform as compared to the younger group, both groups learned the task. However, the density of proliferating (PCNA-positive), differentiating (Dcx-positive), and new neurons (pre-labeled BrdU-positive) was significantly lower in the hippocampus of aged rats as compared to young ones. This inhibition of neurogenesis could be related to increased local production of nitric oxide since the density of neurons expressing neuronal NO-synthase was higher in the aged hippocampus. Thus, we can suggest that an age-related decrease in neurogenesis is not directly associated with place learning in aged rats.

Acute and long-term effects of adolescence stress exposure on rodent adult hippocampal neurogenesis, cognition, and behaviour.

Adolescence represents a critical period for brain and behavioural health and characterised by the onset of mood, psychotic and anxiety disorders. In rodents, neurogenesis is very active during adolescence, when is particularly vulnerable to stress. Whether stress-related neurogenesis changes influence adolescence onset of psychiatric symptoms remains largely unknown. A systematic review was conducted on studies investigating changes in hippocampal neurogenesis and neuroplasticity, hippocampal-dependent cognitive functions, and behaviour, occurring after adolescence stress exposure in mice both acutely (at post-natal days 21-65) and in adulthood. A total of 37 studies were identified in the literature. Seven studies showed reduced hippocampal cell proliferation, and out of those two reported increased depressive-like behaviours, in adolescent rodents exposed to stress. Three studies reported a reduction in the number of new-born neurons, which however were not associated with changes in cognition or behaviour. Sixteen studies showed acutely reduced hippocampal neuroplasticity, including pre- and post-synaptic plasticity markers, dendritic spine length and density, and long-term potentiation after stress exposure. Cognitive impairments and depressive-like behaviours were reported by 11 of the 16 studies. Among studies who looked at adolescence stress exposure effects into adulthood, seven showed that the negative effects of stress observed during adolescence on either cell proliferation or hippocampal neuroplasticity, cognitive deficits and depressive-like behaviour, had variable impact in adulthood. Treating adolescent mice with antidepressants, glutamate receptor inhibitors, glucocorticoid antagonists, or healthy diet enriched in omega-3 fatty acids and vitamin A, prevented or reversed those detrimental changes. Future research should investigate the translational value of these preclinical findings. Developing novel tools for measuring hippocampal neurogenesis in live humans, would allow assessing neurogenic changes following stress exposure, investigating relationships with psychiatric symptom onset, and identifying effects of therapeutic interventions.

274 Early life antibiotic exposure and genetic risk in neurodevelopmental disorders: effects on neurogenesis, the gut microbiome, and behavior

OBJECTIVES/GOALS: Our long-term goal is to understand how both genetic and environmental (GxE) factors contribute to neurodevelopmental disorders (NDDs) so that we may potentially intervene in disease pathogenesis and design therapies to address functional deficiencies. METHODS/STUDY POPULATION: Our studies use a novel GxE model to determine how cephalosporin antibiotic exposure alters the gut microbiome, hippocampal neurogenesis, and behavior in the genetically vulnerable 16p11.2 microdeletion (16pDel) mouse. This mouse models one of the most frequently observed genetic risk variants implicated in NDDs, including ~1% of autism diagnoses. Wildtype and 16pDel littermates were exposed to saline or the cephalosporin, cefdinir, from postnatal days 5-9. We quantified changes in gut microbiota composition using 16S rRNA gene sequencing and utilized immunoblotting, immunohistochemistry, and bulk RNA gene sequencing to assess changes in hippocampal neurogenesis. An additional cohort of saline or cefdinir-exposed mice were subjected to a behavioral battery to assess changes in sociability and anxiety. RESULTS/ANTICIPATED RESULTS: We leveraged the next-generation microbiome bioinformatics platform, Quantitative Insights Into Microbial Ecology 2 (QIIME2) to analyze 16S rRNA gene sequencing datasets of P13 cecal samples from saline- and cefdinir-exposed mice. We found successful perturbations to the gut microbiome following early life cefdinir exposure. Further, we found a robust 50% reduction in hippocampal cyclin E protein in cefdinir-exposed 16pDel male mice, which was replicated in a second independent experiment. This reduction extended to the S-phase cell entry and general stem cell population, quantified by EdU+ and Ki67+ cell numbers, respectively. Lastly, in our first cohort of mice for behavioral studies, we found reduced sociability and increased anxiety-like behaviors in cefdinir-exposed mice. DISCUSSION/SIGNIFICANCE: The findings from this GxE model will provide mechanistic insights into the causes of NDDs; they may inform practice guidelines so as to reduce this environmental exposure; and may suggest interventions like probiotics for those at risk in order to overcome altered gut microbiome composition and restore hippocampal neurogenesis defects.

BKM120 alters the migration of doublecortin-positive cells in the dentate gyrus of mice

BKM120 is an inhibitor of class I phosphoinositide 3-kinases and its anti-cancer effects have been demonstrated in various solid cancer models. BKM120 is highly brain permeable and has been reported to induce mood disturbances in clinical trials. Therefore, we examined whether BKM120 produces anxiety- and depression-like behaviors in mice, as with patients receiving BKM120 in clinical trials. In this study, repeated BKM120 treatment (2.0 or 5.0 mg/kg, i.p., five times at 12-h interval) significantly induced anxiety- and depression-like behaviors in mice. Although abnormal changes in hippocampal neurogenesis have been suggested to, at least in part, associated with the pathogenesis of depression and anxiety, BKM120 did not affect the incorporation of 5-bromo-2′-deoxyuridine or the expression of doublecortin (DCX); however, it significantly enhanced the radial migration of DCX-positive cells in the dentate gyrus. BKM120-induced changes in migration were not accompanied by obvious neuronal damage in the hippocampus. Importantly, BKM120-induced anxiety- and depression-like behaviors were positively correlated with the extent of DCX-positive cell migration. Concomitantly, p-Akt expression was significantly decreased in the dentate gyrus. Moreover, the expression of p-c-Jun N-terminal kinase (JNK), p-DCX, and Ras homolog family member A (RhoA)-GTP decreased significantly, particularly in aberrantly migrated DCX-positive cells. Together, the results suggest that repeated BKM120 treatment enhances the radial migration of DCX-positive cells and induces anxiety- and depression-like behaviors by regulating the activity of Akt, JNK, DCX, and RhoA in the dentate gyrus. It also suggests that the altered migration of adult-born neurons in the dentate gyrus plays a role in mood disturbances.

Adult hippocampal neurogenesis and its impairment in Alzheimer's disease.

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer’s disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD.

A Preclinical Study of Standard Versus Accelerated Transcranial Magnetic Stimulation for Depression in Adolescents.

Objective: Ongoing studies are focused on adapting transcranial magnetic stimulation (TMS) for the treatment of major depressive disorder in adolescent humans. Most protocols in adolescent humans to date have delivered daily 10 Hz prefrontal stimulation with mixed results. Novel TMS dosing strategies such as accelerated TMS have recently been considered. There are knowledge gaps related to the potential clinical and pragmatic advantages of accelerated TMS. This pilot study compared the behavioral effects of a standard daily and accelerated low-intensity TMS (LI-TMS) protocol in an adolescent murine model of depression. Methods: Male adolescent Sprague Dawley rats were placed in transparent plexiglass tubes for 2.5 hours daily for 13 days as part of a study to validate the chronic restraint stress (CRS) protocol. Rats subsequently received 10 minutes of active or sham 10 Hz LI-TMS daily for 2 weeks (standard) or three times daily for 1 week (accelerated). Behavior was assessed using the elevated plus maze and forced swim test (FST). Hippocampal neurogenesis was assessed by injection of the thymidine analogue 5-ethynyl-2'-deoxyuridine at the end of LI-TMS treatment (2 weeks standard, 1 week accelerated), followed by postmortem histological analysis. Results: There were no significant differences in behavioral outcomes among animals receiving once-daily sham or active LI-TMS treatment. However, animals treated with accelerated LI-TMS demonstrated significant improvements in behavioral outcomes compared with sham treatment. Specifically, animals receiving active accelerated treatment showed greater latency to the first immobility behavior (p < 0.05; active: 130 ± 46 seconds; sham: 54 ± 39 seconds) and increased climbing behaviors (p < 0.05; active: 16 ± 5; sham: 9 ± 5) during FST. There were no changes in hippocampal neurogenesis nor any evidence of cell death in histological sections. Conclusions: An accelerated LI-TMS protocol outperformed the standard (once-daily) protocol in adolescent male animals with depression-like behaviors induced by CRS and was not accompanied by any toxicity or tolerability concerns. These preliminary findings support the speculation that novel TMS dosing strategies should be studied in adolescent humans and will inform future clinical protocols.

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.

Cannabinoid receptor 2 deficiency enhances isoflurane-induced spatial cognitive impairment in adult mice by affecting neuroinflammation, neurogenesis and neuroplasticity.

Isoflurane (Iso) is a commonly used inhalational anesthetic and is associated with the incidence of postoperative cognitive dysfunction (POCD). Cannabinoid receptor 2 (CB2R) was previously reported to have a promising neuroprotective function in cases of POCD, but the specific mechanisms have remained to be fully explored. The aim of the present study was to investigate the effect of CB2R deficiency on spatial cognitive performance in adult mice exposed to Iso. A total of 20 adult CB2R knockout (KO) and 20 wild-type (WT) mice were exposed to Iso (1.4% in oxygen for 4 h) or 100% oxygen. The Morris water maze (MWZ) test was performed 10 days after Iso exposure. Immunofluorescence staining and reverse transcription-quantitative PCR were performed to assess the expression of microglial marker ionized calcium-binding adaptor molecule-1 (Iba1) and the mRNA expression levels of microglial phenotype markers (M1: Interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase; M2: Chitinase-3 like protein) in the hippocampus. Changes in hippocampal neurogenesis and neuroplasticity were assessed by 5-bromodeoxyuridine (BrdU) immunostaining and Golgi staining. Compared with control mice, WT Iso-exposed mice had impaired spatial performance in the MWZ test. Furthermore, hippocampal Iba1 immunoreactivity and the number of microglial branches were notably increased in Iso-exposed WT mice. This was paralleled by significant upregulation of M1-associated markers and downregulation of M2-associated markers in the hippocampus. An obviously reduced number of BrdU+ neurons and decreased spine density were observed in WT Iso-exposed mice compared with control mice. Of note, CB2R deficiency exacerbated the spatial cognition impairment induced by Iso in the MWZ test. The alterations in the activation, morphology and M1 polarization of microglia, the number of BrdU+ neurons and spine density were more pronounced in CB2R-deficient Iso-exposed KO mice than in WT Iso-exposed mice. These results suggested that CB2R has a crucial role in Iso-induced cognitive impairment, which may be related to changes in hippocampal neuroinflammation, neurogenesis and neuroplasticity.

Photoperiodic changes in hippocampal neurogenesis and plasma metabolomic profiles in relation to depression-like behavior in mice

Photoperiod alters affective behaviors and brain neuroplasticity in several mammalian species. We addressed whether neurogenesis and signaling pathways of insulin-like growth factor-I (IGF-I), a key modulator of neuroplasticity, are regulated by photoperiod in C57BL/6 J mice, a putative model of seasonal affective disorder. We also examined the effects of photoperiod on plasma metabolomic profiles in relation to depression-like behavior to understand a possible linkage between peripheral metabolism and behavior. Mice that were maintained under long-day conditions (LD) exhibited a higher number of 5-bromo-2′-deoxyuridine-positive cells and higher levels of astrocyte marker in the dentate gyrus of the hippocampus compared to that of mice under short-day conditions (SD). Plasma IGF-I levels and levels/expression of IGF-I signaling molecules in the hippocampus (Brn-4, NeuroD1, and phospho-Akt) involved in neuronal proliferation and differentiation were higher in the mice under LD. Metabolome analysis using plasma of the mice under LD and SD identified several metabolites that were highly correlated with immobility in the forced swim test, a depression-like behavior. Negative correlations with behavior occurred in the levels of 23 metabolites, including metabolites related to neurogenesis and antidepressant-like effects of exercise, metabolites in the biosynthesis of arginine, and the occurrence of branched chain amino acids. Three metabolites had positive correlations with the behavior, including guanidinosuccinic acid, a neurotoxin. Taken together, photoperiodic responses of neurogenesis and neuro-glial organization in the hippocampus may be involved in photoperiodic alteration of depression-like behavior, mediated through multiple pathways, including IGF-I and peripheral metabolites.

Neuroinflammation Induction and Alteration of Hippocampal Neurogenesis in Mice Following Developmental Exposure to Gossypol.

BackgroundNeurogenesis in the neonatal period involves the proliferation and differentiation of neuronal stem/progenitor cells and the establishment of synaptic connections. This process plays a critical role in determining the normal development and maturation of the brain throughout life. Exposure to certain physical or chemical factors during the perinatal period can lead to many neuropathological defects that cause high cognitive dysfunction and are accompanied by abnormal hippocampal neurogenesis and plasticity. As an endocrine disruptor, gossypol is generally known to exert detrimental effects in animals exposed under experimental conditions. However, it is unclear whether gossypol affects neurogenesis in the hippocampal dentate gyrus during early developmental stages.MethodsPregnant Institute of Cancer Research mice were treated with gossypol at a daily dose of 0, 20, and 50 mg/kg body weight from embryonic day 6.5 to postnatal day (P) 21. The changes of hippocampal neurogenesis as well as potential mechanisms were investigated by 5-bromo-2-deoxyuridine labeling, behavioral tests, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western-blot analyses.ResultsAt P8, maternal gossypol exposure impaired neural stem cell proliferation in the dentate gyrus and decreased the number of newborn cells as a result of reduced proliferation of BLBP+ radial glial cells and Tbr2+ intermediate progenitor cells. At P21, the numbers of NeuN+ neurons and parvalbumin+ γ-aminobutyric acid-ergic interneurons were increased following 50 mg/kg gossypol exposure. In addition, gossypol induced hippocampal neuroinflammation, which may contribute to behavioral abnormalities and cognitive deficits and decrease synaptic plasticity.ConclusionsOur findings suggest that developmental gossypol exposure affects hippocampal neurogenesis by targeting the proliferation and differentiation of neuronal stem/progenitor cells, cognitive functions, and neuroinflammation. The present data provide novel insights into the neurotoxic effects of gossypol on offspring.

N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury.

Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.

Differential effects of trancranial magnetic stimulation and electroconvulsive stimulation on adult hippocampal neurogenesis in mice

The neurogenic theory of electroconvulsive therapy (ECT) states that the induction of hippocampal neurogenesis is one of the biological mechanisms responsible for ECT’s antidepressant effects. Hippocampal neurogenesis has been shown to be required for antidepressant effect, is negatively regulated by stress, and electroconvulsive stimulation very potently increases neurogenesis. To confirm and further elucidate specific changes in hippocampal neurogenesis, we examined the timeline of neurogenesis following ECS in an animal model, and expanded the theory to include neurogenesis changes following excitatory transcranial magnetic stimulation (eTMS, 10 Hz) and intermittent theta burst stimulation (iTBS). In mice, we used bromodeoxyuridine (BrdU) to label neurons born two days prior to a single ECS, eTMS or iTBS treatment. Numbers of surviving BrdU+ cells, and proliferating PCNA+ cells, were examined 1, 3, and 7 days following neurostimulation. We found that just one session of ECS increased the number of BrdU positive cells significantly immediately starting on day 1 and declining back to baseline on day 3 and 7. Proliferating PCNA+ cell levels were similar to shams on day 1, peaked on day 3, and declined to basal levels on day 7. The data indicates that there is a delayed and transient increase in neuronal proliferation following ECS, and a loss of earlier-born cells that may be due to neuronal death to counteract the proliferating cell increase. In contrast, eTMS had no effect on levels of neurogenesis across time, suggesting that it does not exert its effects through increasing neurogenesis. Finally, iTBS immediately increased neurogenesis but the number of newborn cells declined over 7 days to levels comparable to sham and eTMS animals. Collectively, we found that different neurostimulation techniques have distinct effects on hippocampal neurogenesis. Ongoing work is examining the effects of chronic neurostimulation on neurogenesis levels and the morphology of newborn neurons.

Acth-induced model of depression resistant to tricyclic antidepressants: Neuroendocrine and behavioral changes and influence of long-term magnesium administration

Magnesium (Mg), is not only a modulator of the glutamatergic NMDA receptors' affinity, it also prevents HPA axis hyperactivity, thus possibly being implicated in neurobiological features of mood disorders. Further uncovering of molecular mechanisms underlying magnesium's proposed effects is needed due to the recent shift in research of treatment resistant depression (TRD) towards glutamatergic pathways. Here, we applied Mg via drinking water for 28 days (50 mg/kg/day), in ACTH-treated rats, an established animal model of depression resistant to tricyclic antidepressants. Using this model in male rats we measured (1) changes in hippocampal neurogenesis and behavioral alterations, (2) adrenal hormones response to acute stress challenge and (3) levels of biometals involved in regulation of monoamines turnover in rat prefrontal cortex. Our results support beneficial behavioral impact of Mg in TRD model together with increased hippocampal neurogenesis and BDNF expression. Furthermore, Mg prevented ACTH-induced disruption in HPA axis function, by normalizing the levels of plasma ACTH, corticosterone and interleukin-6, and by increasing the peripheral release of adrenaline, noradrenaline and serotonin after the acute stress challenge. Finally, the influence on copper/zinc ratio suggested probable magnesium's involvement in monoamine turnover in PFC. Our findings provide further insights into the possible pathways implicated in the behavioral modulation effects of Mg, as well as its central and peripheral effects in ACTH-induced TRD model. Thus, further investigation of molecular signaling related to the glutamatergic transmission and role of Mg, could reveal prospects to novel treatment strategies that could be of particular importance for patients suffering from TRD.

Effect of long‐term methylphenidate exposure on neurogenesis in the hippocampus

Attention Deficit Hyperactivity Disorder (ADHD) is a brain disorder marked by a pattern of inattention and hyperactivity that disrupts everyday functions. This disorder is commonly treated with the drug methylphenidate (MPH), which inhibits reuptake of the neurotransmitters norepinephrine and dopamine, thereby increasing the levels of these catecholamines in the synaptic cleft. In addition to its therapeutic use, MPH is commonly abused by students to increase focus and wakefulness while studying for exams. In order to better understand the long‐term effects of MPH and its pharmacologic activities, we examined the impact of 4 weeks of MPH treatment on neurogenesis in the hippocampus. Interestingly, both low (1 mg/kg) and high (10 mg/kg) doses of MPH delivered twice daily, increased the rate of neurogenesis after 4 weeks. Neurogenesis was measured using 5′‐ethinyldeoxyuridine (EdU), and mice were subjected to a 2 day methylphenidate‐free washout, injected with EdU, then brains were collected 24 hours later. Additionally, we examined the survival of the new cells 4 weeks after EdU injection; here, half of the mice received injections (saline, 1 mg/kg, and 10 mg/kg MPH) for an additional 4 weeks and half were maintained in standard housing with no injections. Mice were sacrificed via transcardial perfusion with 4% paraformaldehyde, and newly generated cells were stained for EdU using Click‐IT chemistry and were double‐labeled using immunohistochemistry for the neuronal marker, NeuN. Cell counts were performed and ratios of EdU+/NeuN+ cells were compared. Although both 1 mg/kg and 10 mg/kg MPH increased the ratio of EdU+/NeuN+ cells, the EdU+/NeuN+ ratios were no different from control (saline) if drug was not continued. Interestingly, if 1 mg/kg MPH was continued for an additional 4 weeks, survival of newly generated cells was enhanced; however, this was not the case for the high dose (10 mg/kg) of MPH. In an effort to investigate the mechanism for MPH‐induced changes in hippocampal neurogenesis, we investigated the levels of several proteins linked to cell growth and survival in the hippocampus, including brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB, the receptor for BDNF), and beta‐catenin. For these studies, mice were divided into 6 cohorts: 2 groups receiving 10 mg/kg of MPH for 4 or 8 weeks, 2 groups receiving 1mg/kg for 4 or 8 weeks, and 2 control groups injected with saline for 4 or 8 weeks. All 6 groups were injected twice a day, 5 days a week. After either 4 weeks or 8 weeks, mice were decapitated, brains dissected, and tissues were flash‐frozen in liquid nitrogen. Then, levels of BDNF or GDNF were examined using enzyme‐linked immunosorbent assays (ELISAs), and VEGF, TrkB, and beta‐catenin expression was investigated using simple western. Interestingly, 1 mg/kg MPH appears to increase VEGF, TrkB, and beta catenin after 4 weeks. In the animals treated with 10 mg/kg MPH, despite the observed increases in neurogenesis after 4 weeks of treatment, beta catenin levels were decreased compared to control at 4 weeks, and VEGF, TrkB, and beta catenin levels were decreased at 8 weeks. In conclusion, long‐term exposure to MPH increases neurogenesis rate in the hippocampus; this effect with low doses of MPH may be related to the increased expression of VEGF, TrkB, and beta catenin.Support or Funding InformationThis research was supported by the ETSU Research Development Committee and the Department of Pharmaceutical Sciences.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.