Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions.

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2-9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

Scavenging Tumor Necrosis Factor α Does Not Affect Inhibition of Dentate Granule Cells Following In Vitro Entorhinal Cortex Lesion.

Neurons that lose part of their afferent input remodel their synaptic connections. While cellular and molecular mechanisms of denervation-induced changes in excitatory neurotransmission have been identified, little is known about the signaling pathways that control inhibition in denervated networks. In this study, we used mouse entorhino-hippocampal tissue cultures of both sexes to study the role of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) in denervation-induced plasticity of inhibitory neurotransmission. In line with our previous findings in vitro, an entorhinal cortex lesion triggered a compensatory increase in the excitatory synaptic strength of partially denervated dentate granule cells. Inhibitory synaptic strength was not changed 3 days after the lesion. These functional changes were accompanied by a recruitment of microglia in the denervated hippocampus, and experiments in tissue cultures prepared from TNF-reporter mice [C57BL/6-Tg(TNFa-eGFP)] showed increased TNFα expression in the denervated zone. However, inhibitory neurotransmission was not affected by scavenging TNFα with a soluble TNF receptor. In turn, a decrease in inhibition, i.e., decreased frequencies of miniature inhibitory postsynaptic currents, was observed in denervated dentate granule cells of microglia-depleted tissue cultures. We conclude from these results that activated microglia maintain the inhibition of denervated dentate granule cells and that TNFα is not required for the maintenance of inhibition after denervation.

Life-long brain compensatory responses to galactic cosmic radiation exposure.

Galactic cosmic radiation (GCR) composed of high-energy, heavy particles (HZE) poses potentially serious hazards to long-duration crewed missions in deep space beyond earth's magnetosphere, including planned missions to Mars. Chronic effects of GCR exposure on brain structure and cognitive function are poorly understood, thereby limiting risk reduction and mitigation strategies to protect against sequelae from exposure during and after deep-space travel. Given the selective vulnerability of the hippocampus to neurotoxic insult and the importance of this brain region to learning and memory, we hypothesized that GCR-relevant HZE exposure may induce long-term alterations in adult hippocampal neurogenesis, synaptic plasticity, and hippocampal-dependent learning and memory. To test this hypothesis, we irradiated 3-month-old male and female mice with a single, whole-body dose of 10, 50, or 100 cGy 56Fe ions (600 MeV, 181 keV/µm) at Brookhaven National Laboratory. Our data reveal complex, dynamic, time-dependent effects of HZE exposure on the hippocampus. Two months post exposure, neurogenesis, synaptic plasticity and learning were impaired compared to sham-irradiated, age-matched controls. By six months post-exposure, deficits in spatial learning were absent in irradiated mice, and synaptic potentiation was enhanced. Enhanced performance in spatial learning and facilitation of synaptic plasticity in irradiated mice persisted 12 months post-exposure, concomitant with a dramatic rebound in adult-born neurons. Synaptic plasticity and spatial learning remained enhanced 20 months post-exposure, indicating a life-long influence on plasticity and cognition from a single exposure to HZE in young adulthood. These findings suggest that GCR-exposure can persistently alter brain health and cognitive function during and after long-duration travel in deep space.

Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Hippocampal deletion of NaV1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome.

Dravet Syndrome is a severe childhood epileptic disorder caused by haploinsufficiency of the SCN1A gene encoding brain voltage-gated sodium channel NaV1.1. Symptoms include treatment-refractory epilepsy, cognitive impairment, autistic-like behavior, and premature death. The specific loci of NaV1.1 function in the brain that underlie these global deficits remain unknown. Here we specifically deleted Scn1a in the hippocampus using the Cre-Lox method in weanling mice. Local gene deletion caused selective reduction of inhibitory neurotransmission measured in dentate granule cells. Mice with local NaV1.1 reduction had thermally evoked seizures and spatial learning deficits, but they did not have abnormalities of locomotor activity or social interaction. Our results show that local gene deletion in the hippocampus can induce two of the most severe dysfunctions of Dravet Syndrome: Epilepsy and cognitive deficit. Considering these results, the hippocampus may be a potential target for future gene therapy for Dravet Syndrome.

Resistance-exercise training ameliorates LPS-induced cognitive impairment concurrent with molecular signaling changes in the rat dentate gyrus.

Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNF-α (~400%) and IL-1ß (~1,500%) mRNA (P < 0.0001) after 6 wk. Five days after LPS injections, half of LPS-injected rats performed RT by ladder climbing for 6 wk, 3 days/wk, whereas half remained without ladders. RT for 6 wk increased lean body mass percentage (P < 0.05), individual muscle masses (gastrocnemius and tibialis anterior) (P < 0.05), and maximum lifting capacity (P < 0.001). The RT group, compared with sedentary controls, had 1) ameliorated spatial learning deficits (P < 0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, protein kinase B, and GSK-3ß proteins (P < 0.05), components of downstream IGF-1 signaling, and 3) increased dentate gyrus synaptic plasticity marker synapsin protein (P < 0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-wk training duration, phosphorylation of ERK1/2 and GSK-3ß proteins, as well as proliferation marker protein, PCNA, were significantly increased (P < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus. NEW & NOTEWORTHY The data suggest that resistance-exercise training restores cognitive deficits induced by lipopolysaccharides and can activate associated IGF-1 signaling in the dentate gyrus. Our data show, for the first time, that as few as three resistance-exercise workouts (spread over 1 wk) can activate IGF-1 downstream signaling and increase proliferation marker PCNA in the dentate gyrus.

Early detonation by sprouted mossy fibers enables aberrant dentate network activity.

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, relatively large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an "early detonation" mode and an increased probability of release compared with mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release, thus facilitating reverberant circuit activity.

Progesterone treatment in rats after severe global cerebral ischemia promotes hippocampal dentate gyrus neurogenesis and functional recovery.

OBJECTIVE: Rats treated with progesterone (P4) after ischemia show an adequate functional performance despite a significant loss of hippocampal pyramidal neurons, suggesting that P4 could favour a permissive microenvironment for cerebral plasticity mechanisms. The possibility of P4 treatment promoting the survival of newly generated hippocampal neurons, in relation to the performance of ischemic rats in a spatial learning task, was assessed in this study. METHODS: Adult male rats were subjected to a severe global cerebral ischemia episode (30 min) and treated with P4 or its vehicle at 15 min, 2, 6, 24, 48 and 72 h of reperfusion. From day 4 to 8 post-ischemia 5-bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells. Twenty-one days post-ischemia, the rats were exposed to the Morris water maze to assess behavioral parameters of spatial learning and memory. Subsequently, the brain was perfusion-fixed and immunofluorescence procedures were performed to quantify the number of new mature neurons (BrdU+/NeuN+) in the dentate gyrus (DG) of the hippocampus. RESULTS: Rats subjected to severe global cerebral ischemia and treated with P4 had a significantly better performance in spatial learning-memory tests, than those treated with vehicle, and a significantly higher number of new mature neurons (BrdU+/NeuN+) in the DG. CONCLUSION: These findings show that post-ischemia P4 treatment, following an episode of severe global cerebral ischemia, promotes the survival of newly generated hippocampal neurons in the DG, which may be one of the mechanisms of cerebral plasticity induced by the hormone, that underlie a successful functional performance in learning and memory tests.

Effect of Acute Stress on the Expression of BDNF, trkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability/Resistance to Stress-Induced Depression.

The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in the pathophysiology of depression, we aimed at assessing the effects of acute stress, i.e., forced swimming (FS), on the expression of brain-derived neurotrophic factor (BDNF), its trkB receptor, and the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the dorsal (dHC) and ventral (vHC) hippocampus of the RHA and the RLA rats, by means of western blot and immunohistochemical assays. A 15 min session of FS elicited different changes in the expression of BDNF in the dHC and the vHC. In RLA rats, an increment in the CA2 and CA3 subfields of the dHC, and a decrease in the CA1 and CA3 subfields and the dentate gyrus (DG) of the vHC, was observed. On the other hand, in the RHA rats, no significant changes in the BDNF levels was seen in the dHC and there was a decrease in the CA1, CA3, and DG of the vHC. Line-related changes were also observed in the expression of trkB and PSA-NCAM. The results are consistent with the hypothesis that the differences in the BDNF/trkB signaling and neuroplastic mechanisms are involved in the susceptibility of RLA rats and resistance of RHA rats to stress-induced depression.

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.

Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.

Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis.

Early-life stress is an established risk for the development of psychiatric disorders. Post-weaning isolation rearing of rats produces lasting developmental changes in behavior and brain function that may have translational pathophysiological relevance to alterations seen in schizophrenia, but the underlying mechanisms are unclear. Accumulating evidence supports the premise that gut microbiota influence brain development and function by affecting inflammatory mediators, the hypothalamic-pituitaryadrenal axis and neurotransmission, but there is little knowledge of whether the microbiota-gut-brain axis might contribute to the development of schizophrenia-related behaviors. To this end the effects of social isolation (SI; a well-validated animal model for schizophrenia)-induced changes in rat behavior were correlated with alterations in gut microbiota, hippocampal neurogenesis and brain cytokine levels. Twenty-four male Lister hooded rats were housed in social groups (group-housed, GH, 3 littermates per cage) or alone (SI) from weaning (post-natal day 24) for four weeks before recording open field exploration, locomotor activity/novel object discrimination (NOD), elevated plus maze, conditioned freezing response (CFR) and restraint stress at one week intervals. Post-mortem caecal microbiota composition, cortical and hippocampal cytokines and neurogenesis were correlated to indices of behavioral changes. SI rats were hyperactive in the open field and locomotor activity chambers traveling further than GH controls in the less aversive peripheral zone. While SI rats showed few alterations in plus maze or NOD they froze for significantly less time than GH following conditioning in the CFR paradigm, consistent with impaired associative learning and memory. SI rats had significantly fewer BrdU/NeuN positive cells in the dentate gyrus than GH controls. SI rats had altered microbiota composition with increases in Actinobacteria and decreases in the class Clostridia compared to GH controls. Differences were also noted at genus level. Positive correlations were seen between microbiota, hippocampal IL-6 and IL-10, conditioned freezing and open field exploration. Adverse early-life stress resulting from continuous SI increased several indices of 'anxiety-like' behavior and impaired associative learning and memory accompanied by changes to gut microbiota, reduced hippocampal IL-6, IL-10 and neurogenesis. This study suggests that early-life stress may produce long-lasting changes in gut microbiota contributing to development of abnormal neuronal and endocrine function and behavior which could play a pivotal role in the aetiology of psychiatric illness.

Decreased hippocampal brain-derived neurotrophic factor and impaired cognitive function by hypoglossal nerve transection in rats.

The hypoglossal nerve controls tongue movements, and damages of it result in difficulty in mastication and food intake. Mastication has been reported to maintain hippocampus-dependent cognitive function. This study was conducted to examine the effect of tongue motor loss on the hippocampus-dependent cognitive function and its underlying mechanism. Male Sprague Dawley rats were subjected to the initial training of Morris water maze task before or after the bilateral transection of hypoglossal nerves (Hx). When the initial training was given before the surgery, the target quadrant dwelling time during the probe test performed at a week after the surgery was significantly reduced in Hx rats relative to sham-operated controls. When the initial training was given after the surgery, Hx affected the initial and reversal trainings and probe tests. Brain-derived neurotrophic factor (BDNF) expression, cell numbers and long-term potentiation (LTP) were examined in the hippocampus on the 10th day, and BrdU and doublecortin staining on the 14th day, after the surgery. Hx decreased the hippocampal BDNF and cells in the CA1/CA3 regions and impaired LTP. BrdU and doublecortin staining was decreased in the dentate gyrus of Hx rats. Results suggest that tongue motor loss impairs hippocampus-dependent cognitive function, and decreased BDNF expression in the hippocampus may be implicated in its underlying molecular mechanism in relation with decreased neurogenesis/proliferation and impaired LTP.

Seizure severity-dependent selective vulnerability of the granule cell layer and aberrant neurogenesis in the rat hippocampus.

The pilocarpine-induced status epilepticus rodent model has been commonly used to analyze the mechanisms of human temporal lobe epilepsy. Recent studies using this model have demonstrated that epileptic seizures lead to increased adult neurogenesis of the dentate granule cells, and cause abnormal cellular organization in dentate neuronal circuits. In this study, we examined these structural changes in rats with seizures of varying severity. In rats with frequent severe seizures, we found a clear loss of Prox1 and NeuN expression in the dentate granule cell layer (GCL), which was confined mainly to the suprapyramidal blade of the GCL at the septal and middle regions of the septotemporal axis of the hippocampus. In the damaged suprapyramidal region, the number of immature neurons in the subgranular zone was markedly reduced. In contrast, in rats with less frequent severe seizures, there was almost no loss of Prox1 and NeuN expression, and the number of immature neurons was increased. In rats with no or slight loss of Prox1 expression in the GCL, ectopic immature neurons were detected in the molecular layer of the suprapyramidal blade in addition to the hilus, and formed chainlike aggregated structures along the blood vessels up to the hippocampal fissure, suggesting that newly generated neurons migrate at least partially along blood vessels to the hippocampal fissure. These results suggest that seizures of different severity cause different effects on GCL damage, neurogenesis, and the migration of new neurons, and that these structural changes are selective to subdivisions of the GCL and the septotemporal axis of the hippocampus.

Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels.

Pain is a critical component hindering recovery and regaining of function after surgery, particularly in the elderly. Understanding the role of pain signaling after surgery may lead to novel interventions for common complications such as delirium and postoperative cognitive dysfunction. Using a model of tibial fracture with intramedullary pinning in male mice, associated with cognitive deficits, we characterized the effects on the primary somatosensory system. Here we show that tibial fracture with pinning triggers cold allodynia and up-regulates nerve injury and inflammatory markers in dorsal root ganglia (DRGs) and spinal cord up to 2 wk after intervention. At 72 h after surgery, there is an increase in activating transcription factor 3 (ATF3), the neuropeptides galanin and neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), as well as neuroinflammatory markers including ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the fractalkine receptor CX3CR1 in DRGs. Using an established model of complete transection of the sciatic nerve for comparison, we observed similar but more pronounced changes in these markers. However, protein levels of BDNF remained elevated for a longer period after fracture. In the hippocampus, BDNF protein levels were increased, yet there were no changes in Bdnf mRNA in the parent granule cell bodies. Further, c-Fos was down-regulated in the hippocampus, together with a reduction in neurogenesis in the subgranular zone. Taken together, our results suggest that attenuated BDNF release and signaling in the dentate gyrus may account for cognitive and mental deficits sometimes observed after surgery.

Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment.

Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment.

Hippocampal VEGF is necessary for antidepressant-like behaviors but not sufficient for antidepressant-like effects of ketamine in rats.

We investigated the effects of ketamine on both the temporal and spatial profiles of neural precursor cells located in the hippocampus, and on antidepressant-like behaviors in rats. A single dose of ketamine resulted in a significant increase in the number of 5-bromo-2-deoxyuridine-positive (BrdU(+)) cells in the dentate gyrus (DG) of rats at 24h, but not at 28days, after treatment completion. Ketamine caused antidepressant-like behaviors in the forced swim test (FST) and novelty suppressed feeding test (NSFT). Viral-mediated hippocampal knockdown of vascular endothelial growth factor (VEGF) produced depressive-like behaviors in the FST and NSFT, which were partially recovered by ketamine to the level observed in the control group. The behavioral effects of VEGF knock down were accompanied by a decrease in hippocampal neurogenesis, which was also partially recovered by ketamine. Our results suggest that basal hippocampal VEGF expression is necessary for ketamine-induced antidepressant-like behaviors in rats, but ketamine-induced VEGF expression only partially contributes to hippocampal neurogenesis and the antidepressant-like effects of ketamine.

Optogenetic dissection of ictal propagation in the hippocampal-entorhinal cortex structures.

Temporal lobe epilepsy (TLE) is one of the most common drug-resistant forms of epilepsy in adults and usually originates in the hippocampal formations. However, both the network mechanisms that support the seizure spread and the exact directions of ictal propagation remain largely unknown. Here we report the dissection of ictal propagation in the hippocampal-entorhinal cortex (HP-EC) structures using optogenetic methods in multiple brain regions of a kainic acid-induced model of TLE in VGAT-ChR2 transgenic mice. We perform highly temporally precise cross-area analyses of epileptic neuronal networks and find a feed-forward propagation pathway of ictal discharges from the dentate gyrus/hilus (DGH) to the medial entorhinal cortex, instead of a re-entrant loop. We also demonstrate that activating DGH GABAergic interneurons can significantly inhibit the spread of ictal seizures and largely rescue behavioural deficits in kainate-exposed animals. These findings may shed light on future therapeutic treatments of TLE.

Bangle (Zingiber purpureum) Improves Spatial Learning, Reduces Deficits in Memory, and Promotes Neurogenesis in the Dentate Gyrus of Senescence-Accelerated Mouse P8.

Bangle (Zingiber purpureum) is a tropical ginger that is used as a spice in Southeast Asia. Phenylbutenoid dimers isolated from Bangle have exhibited neurotrophic effects in primary cultured rat cortical neurons and PC12 cells. Furthermore, chronic treatment with phenylbutenoid dimers enhances hippocampal neurogenesis in olfactory bulbectomized mice. In this study, we investigated the effects of Bangle extract on behavior and hippocampal neurogenesis in vivo. SAMP8 mice, which are an established model for accelerated aging, with age-related learning and memory impairments, were given a Bangle-containing diet for 1 month, and subsequent behavioral tests and immunohistochemistry for Ki67, a proliferating cell marker, were performed. We found that the Bangle-containing diet improved spatial learning and memory deficits in the Morris water maze and significantly increased the numbers of Ki67-positive cells in the dentate gyrus of the SAMP8 mice. In addition, the Bangle extract exhibited a neurotrophin-like activity as indicated by the induction of neurite sprouting in PC12 cells. Our results suggest that Bangle is beneficial for the prevention of age-related progression of cognitive impairment.

Simvastatin prevents ß-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate.

Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), ß-amyloid (Aß) selectively impairs survival and neurite growth of newborn neurons in the 2(nd) week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in Aß25-35 (3 nmol)-injected (i.c.v.) mice (Aß25-35-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2-14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the α7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the α4ß2nAChR antagonist DHßE. The SV-treatment in Aß25-35-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in Aß25-35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Aß25-35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in Aß25-35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in Aß25-35-mice via reduction of FPP can protect neurogenesis through α7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function.