Mossy Cells in the Dorsal and Ventral Dentate Gyrus Differ in Their Patterns of Axonal Projections.

Mossy cells (MCs) of the dentate gyrus (DG) are a major group of excitatory hilar neurons that are important for regulating activity of dentate granule cells. MCs are particularly intriguing because of their extensive longitudinal connections within the DG. It has generally been assumed that MCs in the dorsal and ventral DG have similar patterns of termination in the inner one-third of the dentate molecular layer. Here, we demonstrate that axonal projections of MCs in these two regions are considerably different. MCs in dorsal and ventral regions were labeled selectively with Cre-dependent eYFP or mCherry, using two transgenic mouse lines (including both sexes) that express Cre-recombinase in MCs. At four to six weeks following unilateral labeling of MCs in the ventral DG, a dense band of fibers was present in the inner one-fourth of the molecular layer and extended bilaterally throughout the rostral-caudal extent of the DG, replicating the expected distribution of MC axons. In contrast, following labeling of MCs in the dorsal DG, the projections were more diffusely distributed. At the level of transfection, fibers were present in the inner molecular layer, but they progressively expanded into the middle molecular layer and, most ventrally, formed a distinct band in this region. Optical stimulation of these caudal fibers expressing ChR2 demonstrated robust EPSCs in ipsilateral granule cells and enhanced the effects of perforant path stimulation in the ventral DG. These findings suggest that MCs in the dorsal and ventral DG differ in the distribution of their axonal projections and possibly their function.SIGNIFICANCE STATEMENT Mossy cells (MCs), a major cell type in the hilus of the dentate gyrus (DG), are unique in providing extensive longitudinal and commissural projections throughout the DG. Although it has been assumed that all MCs have similar patterns of termination in the inner molecular layer of the DG, we discovered that the axonal projections of dorsal and ventral MCs differ. While ventral MC projections exhibit the classical pattern, with dense innervation in the inner molecular layer, dorsal MCs have a more diffuse distribution and expand into the middle molecular layer where they overlap and interact with innervation from the perforant path. These distinct locations and patterns of axonal projections suggest that dorsal and ventral MCs may have different functional roles.

Dentate Gyrus Somatostatin Cells are Required for Contextual Discrimination During Episodic Memory Encoding.

Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

Changes in Glial Support of the Hippocampus during the Development of an Alzheimer's Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1.

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer's disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment.

Tiam1 is Critical for Glutamatergic Synapse Structure and Function in the Hippocampus.

Mounting evidence suggests numerous glutamatergic synapse subtypes exist in the brain, and that these subtypes are likely defined by unique molecular regulatory mechanisms. Recent work has identified substantial divergence of molecular composition between commonly studied Schaffer collateral synapses and perforant path-dentate gyrus (DG) synapses of the hippocampus. However, little is known about the molecular mechanisms that may confer unique properties to perforant path-DG synapses. Here we investigate whether the RhoGEF (Rho guanine-nucleotide exchange factor) protein Tiam1 plays a unique role in the regulation of glutamatergic synapses in dentate granule neurons using a combination of molecular, electrophysiological, and imaging approaches in rat entorhino-hippocampal slices of both sexes. We find that inhibition of Tiam1 function in dentate granule neurons reduces synaptic AMPA receptor function and causes dendritic spines to adopt an elongated filopodia-like morphology. We also find that Tiam1's support of perforant path-DG synapse function is dependent on its GEF domain and identify a potential role for the auto-inhibitory PH domain of Tiam1 in regulating Tiam1 function at these synapses. In marked contrast, reduced Tiam1 expression in CA1 pyramidal neurons produced no effect on glutamatergic synapse development. Together, these data identify a critical role for Tiam1 in the hippocampus and reveal a unique Tiam1-mediated molecular program of glutamatergic synapse regulation in dentate granule neurons.SIGNIFICANCE STATEMENT Several lines of evidence independently point to the molecular diversity of glutamatergic synapses in the brain. Rho guanine-nucleotide exchange factor (RhoGEF) proteins as powerful modulators of glutamatergic synapse function have also become increasingly appreciated in recent years. Here we investigate the synaptic regulatory role of the RhoGEF protein Tiam1, whose expression appears to be remarkably enriched in granule neurons of the dentate gyrus. We find that Tiam1 plays a critical role in the development of glutamatergic perforant path-dentate gyrus synapses, but not in commonly studied in Schaffer collateral-CA1 synapses. Together, these data reveal a unique RhoGEF-mediated molecular program of glutamatergic synapse regulation in dentate granule neurons.

Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction.

Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy. As the dentate's principal signalling population, the granule cells' aggregate excitability has the potential to provide a mechanistically-independent downstream target. We examined whether normalizing epilepsy-associated granule cell hyperexcitability-without correcting the underlying structural circuit disruptions-would constitute an effective therapeutic approach for cognitive dysfunction. In the systemic pilocarpine mouse model of temporal lobe epilepsy, the epileptic dentate gyrus excessively recruits granule cells in behavioural contexts, not just during seizure events, and these mice fail to perform on a dentate-mediated spatial discrimination task. Acutely reducing dorsal granule cell hyperactivity in chronically epileptic mice via either of two distinct inhibitory chemogenetic receptors rescued behavioural performance such that they responded comparably to wild type mice. Furthermore, recreating granule cell hyperexcitability in control mice via excitatory chemogenetic receptors, without altering normal circuit anatomy, recapitulated spatial memory deficits observed in epileptic mice. However, making the granule cells overly quiescent in both epileptic and control mice again disrupted behavioural performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioural performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviours remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviourally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviourally permissive activity window in which the circuit operates. We conclude that restoring appropriate principal cell tuning via circuit-based therapies, irrespective of the mechanisms generating the disease-related hyperactivity, is a promising translational approach.

Targeted hippocampal GABA neuron ablation by Stable Substance P-saporin causes hippocampal sclerosis and chronic epilepsy in rats.

Cryptogenic temporal lobe epilepsy develops in the absence of identified brain injuries, infections, or structural malformations, and in these cases, an unidentified pre-existing abnormality may initiate febrile seizures, hippocampal sclerosis, and epilepsy. Although a role for GABAergic dysfunction in epilepsy is intuitively obvious, no causal relationship has been established. In this study, hippocampal GABA neurons were targeted for selective elimination to determine whether a focal hippocampal GABAergic defect in an otherwise normal brain can initiate cryptogenic temporal lobe epilepsy with hippocampal sclerosis. We used Stable Substance P-saporin conjugate (SSP-saporin) to target rat hippocampal GABA neurons, which selectively and constitutively express the neurokinin-1 receptors that internalize this neurotoxin. Bilateral and longitudinally extensive intrahippocampal microinjections of SSP-saporin caused no obvious behavioral effects for several days. However, starting ~4 days postinjection, rats exhibited episodes of immobilization, abnormal flurries of "wet-dog" shakes, and brief focal motor seizures characterized by facial automatisms and forepaw clonus. These clinically subtle behaviors stopped after ~4 days. Convulsive status epilepticus did not develop, and no deaths occurred. Months later, chronically implanted rats exhibited spontaneous focal motor seizures and extreme hippocampal sclerosis. These data suggest that hippocampal GABAergic dysfunction is epileptogenic and can produce the defining features of cryptogenic temporal lobe epilepsy.

Tanshinone I Enhances Neurogenesis in the Mouse Hippocampal Dentate Gyrus via Increasing Wnt-3, Phosphorylated Glycogen Synthase Kinase-3ß and ß-Catenin Immunoreactivities.

Tanshinone I (TsI), a lipophilic diterpene extracted from Danshan (Radix Salvia miltiorrhizae), exerts neuroprotection in cerebrovascular diseases including transient ischemic attack. In this study, we examined effects of TsI on cell proliferation and neuronal differentiation in the subgranular zone (SGZ) of the mouse dentate gyrus (DG) using Ki-67, BrdU and doublecortin (DCX) immunohistochemistry. Mice were treated with 1 and 2 mg/kg TsI for 28 days. In the 1 mg/kg TsI-treated-group, distribution patterns of BrdU, Ki-67 and DCX positive ((+)) cells in the SGZ were similar to those in the vehicle-treated-group. However, in the 2 mg/kg TsI-treated-group, double labeled BrdU(+)/NeuN(+) cells, which are mature neurons, as well as Ki-67(+), DCX(+) and BrdU(+) cells were significantly increased compared with those in the vehicle-treated-group. On the other hand, immunoreactivities and protein levels of Wnt-3, ß-catenin and serine-9-glycogen synthase kinase-3ß (p-GSK-3ß), which are related with morphogenesis, were significantly increased in the granule cell layer of the DG only in the 2 mg/kg TsI-treated-group. Therefore, these findings indicate that TsI can promote neurogenesis in the mouse DG and that the neurogenesis is related with increases of Wnt-3, p-GSK-3ß and ß-catenin immunoreactivities.

Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.

New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.

Essential oils from two Allium species exert effects on cell proliferation and neuroblast differentiation in the mouse dentate gyrus by modulating brain-derived neurotrophic factor and acetylcholinesterase.

BACKGROUND: In the present study, we investigated the effects of oil products from two Allium species: Allium sativum (garlic) and Allium hookeri (Chinese chives) on cell proliferation and neuroblast differentiation in the mouse dentate gyrus. METHODS: Using corn oil as a vehicle, the essential oil from garlic (10 ml/kg), or Chinese chives (10 ml/kg) was administered orally to 9-week-old mice once a day for 3 weeks. One hour following the last treatment, a novel object recognition test was conducted and the animals were killed 2 h after the test. RESULTS: In comparison to the vehicle-treated group, garlic essential oil (GO) treatment resulted in significantly increased exploration time and discrimination index during the novel object recognition test, while Chinese chives essential oil (CO) reduced the exploration time and discrimination index in the same test. In addition, the number of Ki67-immunoreactive proliferating cells and doublecortin-immunoreactive neuroblasts significantly increased in the dentate gyrus of GO-treated animals. However, administration of CO significantly decreased cell proliferation and neuroblast differentiation. Administration of GO significantly increased brain-derived neurotrophic factor (BDNF) levels and decreased acetylcholinesterase (AChE) activity in the hippocampal homogenates. In contrast, administration of CO decreased BDNF protein levels and had no significant effect on AChE activity, compared to that in the vehicle-treated group. CONCLUSIONS: These results suggest that GO significantly improves novel object recognition as well as increases cell proliferation and neuroblast differentiation, by modulating hippocampal BDNF protein levels and AChE activity, while CO impairs novel object recognition and decreases cell proliferation and neuroblast differentiation, by reducing BDNF protein levels in the hippocampus.

TAR DNA-binding protein 43 pathology in Alzheimer's disease with psychosis.

BACKGROUND: TAR DNA-binding protein 43 (TDP-43) has been identified as a major disease protein in frontotemporal lobar degeneration. More recently, TDP-43 proteinopathy has also been observed in Alzheimer's disease (AD) with a characteristic distribution of TDP-43 predominantly in the mesial temporal lobe, and to a lesser degree in the neocortical areas. AD subjects with psychotic symptoms (AD+P) represent a subgroup characterized by greater impairment of frontal cortex-dependent cognitive functions and more severe frontal cortical neuropathology. The aim of this study is to determine whether there is an association between TDP-43 pathology and AD+P. We hypothesized that TDP-43 pathology would be more frequent in AD+P than in AD without psychosis. METHODS: We studied the presence and distribution of TDP-43 pathology by immunohistochemistry in the dentate gyrus (DG) and prefrontal cortex (FC) of postmortem brain specimens from 68 subjects with a primary neuropathologic diagnosis of AD as determined by the Neuropathology Core of the University of Pittsburgh Alzheimer's Disease Research Center. RESULTS: Forty-five (66%) subjects were classified as AD+P. Fourteen (20.6%) subjects had TDP-43 pathology in DG, eight (11.8%) had TDP-43 pathology in FC, and six (8.8%) had TDP-43 pathology in both regions. TDP-43 in DG was not significantly associated with AD+P. However, TDP-43 in FC demonstrated a trend toward reduced likelihood of psychosis (p = 0.068). TDP-43 pathology in DG, but not FC, was significantly associated with greater age at death and longer duration of illness. CONCLUSIONS: Our findings indicate that there was no association between concomitant TDP-43 pathology in DG or FC and AD+P.

Comparison of α-synuclein immunoreactivity in the hippocampus between the adult and aged beagle dogs.

Alpha-synuclein (α-syn), as a neuroprotein, is expressed in neural tissue, and it is related to a synaptic transmission and neuronal plasticity. In this study, we compared the distribution and immunoreactivity of α-syn and related gliosis in hippocampus between young adult (2-3 years) and aged (10-12 years) beagle dogs. In both groups, α-syn immunoreactivity was detected in neuropil of all the hippocampal sub-regions, but not in neuronal somata. In the aged hippocampus, α-syn immunoreactivity was apparently increased in mossy fibers compared to that in the adult dog. In addition, α-syn protein level was markedly increased in the aged hippocampus. On the other hand, GFAP and Iba-1 immunoreactivity in astrocytes and microglia, respectively, were increased in all the hippocampal sub-regions of the aged group compared to that in the adult group: especially, their immunoreactivity was apparently increased around mossy fibers. In addition, in this study, we could not find any expression of α-syn in astrocytes and microglia. These results indicate that α-syn immunoreactivity apparently increases in the aged hippocampus and that GFAP and Iba-1 immunoreactivity are also apparently increased at the regions with increased α-syn immunoreactivity. This increase in α-syn expression might be a feature of normal aging.

An NCAM mimetic, FGL, alters hippocampal cellular morphometry in young adult (4 month-old) rats.

The neural cell adhesion molecule, NCAM, is ubiquitously expressed within the CNS and has roles in development, cognition, neural plasticity and regulation of the immune system. NCAM is thus potentially an important pharmacological target for treatment of brain diseases. A cell adhesion mimetic FGL, a 15 amino-acid peptide derived from the second fibronectin type-III module of NCAM, has been shown to act as a neuroprotective agent in experimental disease and ageing models, restoring hippocampal/cognitive function and markedly alleviating deleterious changes in the CNS. However, the effects of FGL on the hippocampus of young healthy rats are unknown. The present study has examined the cellular neurobiological consequences of subcutaneous injections of FGL, on hippocampal cell morphometry in young (4 month-old) rats. We determined the effects of FGL on hippocampal volume, pyramidal neuron number/density (using unbiased quantitative stereology), and examined aspects of neurogenesis (using 2D morphometric analyses). FGL treatment reduced total volume of the dorsal hippocampus (associated with a decrease in total pyramidal neuron numbers in CA1 and CA3), and elevated the number of doublecortin immunolabeled neurons in the dentate gyrus, indicating a likely influence on neurogenesis in young healthy rats. These data indicate that FGL has a specific age dependent effect on the hippocampus, differing according to the development and maturity of the CNS.

Neuronal activity dynamics in the dentate gyrus during early epileptogenesis.

Epileptogenesis is a complex process involving a multitude of changes at the molecular, cellular and network level. Previous studies have identified several key alterations contributing to epileptogenesis and the development of hyper-excitability in different animal models, but only a few have focused on the early stages of this process. For post status epilepticus (SE) temporal lobe epilepsy in particular, understanding network dynamics during the early phases might be crucial for developing accurate preventive treatments to block the development of chronic spontaneous seizures. In this study, we used a viral vector mediated approach to examine activity of neurons in the dentate gyrus of the hippocampus during early epileptogenesis. We find that while granule cells are active 8 h after SE and then gradually decrease their activity, Calretinin-positive mossy cells and Neuropeptide Y-positive GABAergic interneurons in the hilus show a delayed activation pattern starting at 24 and peaking at 48 h after SE. These data suggest that indirect inhibition of granule cells by mossy cells through recruitment of local GABAergic interneurons could be an important mechanisms of excitability control during early epileptogenesis, and contribute to our understanding of the complex role of these cells in normal and pathological conditions.

Patterning of retinoic acid signaling and cell proliferation in the hippocampus.

The nuclear receptor ligand retinoic acid (RA) has been identified as an endogenous regulatory factor in the hippocampus, acting on pyramidal neurons and granule neuron progenitors, but almost nothing is known about the distribution of RA itself in the hippocampus. This study describes the source of RA for the rodent hippocampus in the meninges via the key RA synthetic enzyme retinaldehyde dehydrogenase 2 (RALDH2). Diffusion of RA from the meninges potentially creates a gradient of RA across the infrapyramidal and suprapyramidal blades of the dentate gyrus, enhanced by the expression of the RA catabolic enzyme Cyp26B1 between the blades, and an infrapyramidal and suprapyramidal blade difference is evident in RA-regulated transcription. This asymmetry may contribute to some of the physiological and molecular differences between the blades, including a disparity in the rates of cell proliferation in the subgranular zone of the two blades through RA inhibition of cell proliferation. Such differences can be altered by either the application of excess RA, its effect dependent on the relative position along the septotemporal axis, or change in RA signaling through mutation of retinol binding protein, while the capacity of RA to inhibit proliferation of cells in the dentate gyrus is demonstrated using in vitro slice culture. Use of synthetic and catabolic enzymes in the hippocampus to create differing zones of RA concentration parallels the mechanisms used in the developing brain to generate patterns of RA-regulated transcription.

Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice.

Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels.

N (w) -propyl-L-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses.

We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, N (w) -propyl-l-arginine (L-NPA), on kainic acid (KA)-induced status epilepticus (SE) and early epileptogenesis in C57BL/6J mice. SE was induced with 20 mg/kg KA (i.p.) and seizures terminated after 2 h with diazepam (10 mg/kg, i.p). L-NPA (20 mg/kg, i.p.) or vehicle was administered 30 min before KA. Behavioural seizure severity was scored using a modified Racine score and electrographic seizure was recorded using an implantable telemetry device. Neuronal activity, activity-dependent synaptogenesis and reactive gliosis were quantified immunohistochemically, using c-Fos, synaptophysin and microglial and astrocytic markers. L-NPA treatment reduced the severity and duration of convulsive motor seizures, the power of electroencephalogram in the gamma band, and the frequency of epileptiform spikes during SE. It also reduced c-Fos expression in dentate granule cells at 2 h post-KA, and reduced the overall rate of epileptiform spiking (by 2- to 2.5-fold) in the first 7 days after KA administration. Furthermore, treatment with L-NPA suppressed both hippocampal gliosis and activity-dependent synaptogenesis in the outer and middle molecular layers of the dentate gyrus in the early phase of epileptogenesis (72 h post-KA). These results suggest that nNOS facilitates seizure generation during SE and may be important for the neurobiological changes associated with the development of chronic epilepsy, especially in the early stages of epileptogenesis. As such, it might represent a novel target for disease modification in epilepsy.

Melatonin improves D-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression.

Melatonin (N-acetyl-5-methoxytryptamine) has multiple functions. In this study, we investigated the effects of melatonin on memory, cell proliferation, and neuroblast differentiation in the dentate gyrus of a mouse model of D-galactose-induced aging. D-galactose was subcutaneously administered to 7-wk-old mice for 10 wk, and age-matched mice were used as controls. Seven weeks after D-galactose administration, vehicle (water) or melatonin (6 mg/L in water) was administered ad libitum to the mice for 3 wk. The administration of D-galactose significantly increased the escape latency compared with that in the control mice on days 1-3. In addition, cells in the subgranular zone and in the granule cell layer of the dentate gyrus showed severe damage (cytoplasmic condensation) in the D-galactose-treated mice. However, melatonin supplementation to these mice for 3 wk significantly ameliorated the D-galactose-induced increase in escape latency and neuronal damage compared with the vehicle-treated group. The administration of melatonin also significantly restored the D-galactose-induced reduction of proliferating cells (Ki67-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the dentate gyrus. Furthermore, the administration of melatonin significantly increased Ser133-phosphorylated cyclic AMP response element binding protein in the dentate gyrus. The administration of melatonin significantly reduced D-galactose-induced lipid peroxidation in the dentate gyrus. These results suggest that melatonin may be helpful in reducing age-related phenomena in the brain.

Analysis of Differentially Expressed Genes in the Dentate Gyrus and Anterior Cingulate Cortex in a Mouse Model of Depression.

Major depressive disorder (MDD) is a prevalent, chronic, and relapse-prone psychiatric disease. However, the intermediate molecules resulting from stress and neurological impairment in different brain regions are still unclear. To clarify the pathological changes in the dentate gyrus (DG) and anterior cingulate cortex (ACC) regions of the MDD brain, which are the most closely related to the disease, we investigated the published microarray profile dataset GSE84183 to identify unpredictable chronic mild stress- (UCMS-) induced differentially expressed genes (DEGs) in the DG and ACC regions. Based on the DEG data, functional annotation, protein-protein interaction, and transcription factor (TF) analyses were performed. In this study, 1071 DEGs (679 upregulated and 392 downregulated) and 410 DEGs (222 upregulated and 188 downregulated) were identified in DG and ACC, respectively. The pathways and GO terms enriched by the DEGs in the DG, such as cell adhesion, proteolysis, ion transport, transmembrane transport, chemical synaptic transmission, immune system processes, response to lipopolysaccharide, and nervous system development, may reveal the molecular mechanism of MDD. However, the DEGs in the ACC involved metabolic processes, proteolysis, visual learning, DNA methylation, innate immune responses, cell migration, and circadian rhythm. Sixteen hub genes in the DG (Fn1, Col1a1, Anxa1, Penk, Ptgs2, Cdh1, Timp1, Vim, Rpl30, Rps21, Dntt, Ptk2b, Jun, Avp, Slit1, and Sema5a) were identified. Eight hub genes in the ACC (Prkcg, Grin1, Syngap1, Rrp9, Grwd1, Pik3r1, Hnrnpc, and Prpf40a) were identified. In addition, eleven TFs (Chd2, Zmiz1, Myb, Etv4, Rela, Tcf4, Tcf12, Chd1, Mef2a, Ubtf, and Mxi1) were predicted to regulate more than two of these hub genes. The expression levels of ten randomly selected hub genes that were specifically differentially expressed in the MDD-like animal model were verified in the corresponding regions in the human brain. These hub genes and TFs may be regarded as potential targets for future MDD treatment strategies, thus aiding in the development of new therapeutic approaches to MDD.

Excitatory input onto hilar somatostatin interneurons is increased in a chronic model of epilepsy.

The density of somatostatin (SOM)-containing GABAergic interneurons in the hilus of the dentate gyrus is significantly decreased in both human and experimental temporal lobe epilepsy. We used the pilocarpine model of status epilepticus and temporal lobe epilepsy in mice to study anatomical and electrophysiological properties of surviving somatostatin interneurons and determine whether compensatory functional changes occur that might offset loss of other inhibitory neurons. Using standard patch-clamp techniques and pipettes containing biocytin, whole cell recordings were obtained in hippocampal slices maintained in vitro. Hilar SOM cells containing enhanced green fluorescent protein (EGFP) were identified with fluorescent and infrared differential interference contrast video microscopy in epileptic and control GIN (EGFP-expressing Inhibitory Neurons) mice. Results showed that SOM cells from epileptic mice had 1) significant increases in somatic area and dendritic length; 2) changes in membrane properties, including a small but significant decrease in resting membrane potential, and increases in time constant and whole cell capacitance; 3) increased frequency of slowly rising spontaneous excitatory postsynaptic currents (sEPSCs) due primarily to increased mEPSC frequency, without changes in the probability of release; 4) increased evoked EPSC amplitude; and 5) increased spontaneous action potential generation in cell-attached recordings. Results suggest an increase in excitatory innervation, perhaps on distal dendrites, considering the slower rising EPSCs and increased output of hilar SOM cells in this model of epilepsy. In sum, these changes would be expected to increase the inhibitory output of surviving SOM interneurons and in part compensate for interneuronal loss in the epileptogenic hippocampus.

Epigenetic regulation of neurogenesis in the adult hippocampus.

The dentate gyrus of the hippocampus is an exception to a 'neurogenesis-unfriendly' environment of the adult brain. New functional neurons generated in this region contribute to learning and mood regulation, and thus represent a unique form of neural plasticity. The rate of hippocampal neurogenesis significantly changes on physiological or pathological influences, such as physical activity, environmental enrichment, stress, and aging. We suggest that epigenetic mechanisms could be sensors of environmental changes and fine modulators of adult hippocampal neurogenesis. Here, we examine the role of DNA methylation and methylation of core histones mediated by the Polycomb and Trithorax complexes in the regulation of adult neurogenesis. Given the recent surprising discovery of dynamic and reversible DNA methylation in the hippocampus, we speculate regarding its regulation and its role in adult neurogenesis.