Aims/Purpose: Despite significant advances in neuroprotection strategies, patients are still at high risk for glaucoma neurodegeneration (GND), in which neuroinflammation (NINF) is exceedingly implicated. It has recently been shown that in the acute phase, NINF cascades lead to apoptosis, meanwhile in later stages a wide variety of signalling pathways act trying to repair existing damage. Also, NINF affects adult neurogenesis (NG), that, in turns, remains an unknown field to be explored in GND.Methods: A total of 135 participants of both sexes, aged 35–80 years, were selected and classified into: open‐angle glaucoma (OAG) patients (n = 70) and healthy controls (CG; n = 65). Demographics, clinical and molecular data were registered. Tears were collected from the inferior meniscus and frozen at −80°C until processing by the multiplex system (human cytokine panel) to determine the cytokine/chemokine levels. Data were processed by using the IBM SPSS 25.0 program.Results: Mean age of the participants was 62 ± 14 years (68% were aged over 60 years). Gender distribution was 38% males/62% females. Tears from patients with OAG showed differential expression profile of the assayed cytokines/chemokines, as compared to the CG. Specifically, the granulocyte‐macrophage colony stimulating factor (GM‐CSF; p < 0.001), interferon‐γ (IFN‐γ; p < 0.001), tumour necrosis factor alpha (TNFa); and interleukin (IL) ‐4 and − 10 (p < 0.05) revealed significantly higher levels in the OAG patients versus the CG.Conclusions: Liberation of anti‐ and pro‐inflammatory cytokines with a broad range of functions in adult NG, as the aforementioned factors: the GM‐CSF, INFg, TNFa, IL‐4 and IL‐10, can be fully considered when managing GND and visual outcomes.

Rotating shift work, irregular sleep patterns and jetlag disrupt circadian rhythms, induce or aggravate disease, and produce deficits in cognitive function. Internal misalignment, a state in which abnormal phase relationships prevail between and within organs, is widely proposed to account for these adverse effects of circadian disruption. This hypothesis has been difficult to test because phase shifts of the entraining environmental cycle lead to transient desynchrony. Thus, it remains possible that phase shifts, regardless of internal desynchrony, account for adverse effects of circadian disruption. I have used the duper mutant hamster, whose locomotor activity rhythms re-entrain 5-fold faster than wild types after a phase shift of 8 hours, to test whether internal desynchrony can account for adverse effects of jet lag on adult neurogenesis. I subjected wild type and duper female hamsters to alternating 8h phase advances and delays of the LD cycle at 16-day intervals. I injected 5-Bromo-2’-deoxyuridine (BrdU, a thymidine analogue) after the 4th shift and collected brains after the 8th shift. As expected, mutants re-entrained activity rhythms more rapidly than did wild types. On the other hand, estrous cycles, as assessed by vaginal smears, were rarely disrupted by repeated phase shifts in either genotype. I next compared cell proliferation and neurogenesis in the subgranular zone of the hippocampus between Duper mutants and wild type siblings using the S-phase marker BrdU and the neuronal marker NeuN. I assessed the total number of BrdU cells in the subgranular zone of the hippocampus, as the proportion that expressed NeuN. Duper mutants had more BrdU-ir cells, and more BrdU+/NeuN+ cells than did wild types, whether or not they experienced phase shifts, revealing an unexpected increase in neurogenesis. Surprisingly, repeated phase shifts increased neurogenesis in WT but not duper hamsters. Despite the increase in neurogenesis, phase shifts reduced the number of adult-born non-neuronal (BrdU+/NeuN-) cells in WT hamsters but had no such effect on duper mutants. In addition, the duper mutation increases hippocampal neurogenesis regardless of circadian. Our results suggest that adult-born non-neuronal cells are most vulnerable to circadian disruption, and that internal desynchrony promotes their demise. disruption.

Platelets play a key role in hemostasis and are involved in various disease mechanisms, including the disorders of the Central Nervous System. In a surprising way, platelets have several overlapping features with neurons, such as similar subcellular organization, corresponding secretion mechanisms, common expression of proteins etc. Additionally, platelets seem to communicate directly with neuronal cells and to be involved in processes, such as bioactive molecules’ transfer to brain and the adult neurogenesis that occurs mainly in the brain hippocampus, which is essential for synaptic plasticity’s maintaining and regulation of memory and learning abilities. For half a century, platelets have been proposed to serve as an alternative neuronal model and an easily accessible way to study various neurological disorders. Depression and Alzheimer disease are the most studied so far, while the research range to almost every neurological disorder, including those associated with learning and/or cognitive impairments such as Autism Spectrum Disorders and Attention deficit Hyperactivity Disorder. The multidimensional effect of platelets in both brain function and pathophysiology of neurological disorders have been recognized, related research however remains in early stages. Thus, efforts to develop reliable biomarkers and functional models for the diagnosis and the study of neurobiological disorders has not led to feasible results so far. This dissertation is a bibliographic review of the research data that have been produced to date, investigating the way in which platelets exert their multiple actions in both physiological and pathological neurological conditions, as well as the new prospects in this complex but very promising scientific field.

Traumatic injuries, as well as degenerative diseases of the nervous system, are extremely common nowadays, there- fore, in clinical practice the use new methods for their treatment, such as stimulation of reparative neurogene- sis by growth factors, is highly topical. Aim. To review the published results of the experimental use of various growth factors for reparative neurogenesis stimulation and neuroprotection and to evaluate the prospects for their clinical application. Methods. Publications’ search was carried out in open databases of scientific literature, such as PubMed, Cyberleninka and eLIBRARY.RU based on keywords and their combinations: «reparative neuro- genesis», «neuroprotection», «nervous tissue», «neurotro- phic factors», «growth factors», «implantation» (in Russian and English). The search depth is 20 years. Results. The sti mulating and depressing effects of the neurotrophins NGF, CNTF, NF3, NF4, BDNF, GDNF are analysed, as well as the Shh protein’s impact on the regeneration of neu- rons and glial cells of the central and peripheral nervous systems and the specificity of their action on specific cells. The influence of such nonspecific trophic factors as EGF, FGF, IGF-1, VEGF on the viability of cells of the nervous system is described, the results of the enhancement of neurogenesis by using stimulants of erythropoiesis and retinoic acid are given. The results of using various me- thods of growth factors implantation are demonstrated. Conclusions. In the course of the study, it was found that in recent studies, mainly preclinical, both positive and negative results of the neurotrophins and nonspe- cific growth factors application for stimulating reparative neurogenesis and neuroprotection have been experi- mentally achieved. The specificity of their action on vari- ous neurocytes and the dependence of the effect on the chosen route of administration during therapy are noted. It is concluded that additional research is needed to re- solve the issue of recommending these factors for clinical application.

In both animals and humans, regular exercise improves neurogenesis and cognition. Transfer of blood from young mice to old mice also improves

Genome-Wide Analysis Identifies NURR1-Controlled Network of New Synapse Formation and Cell Cycle Arrest in Human Neural Stem Cells.

Mood disorders, in particular depression, are a major burden of our society. Due to the poor knowledge of the biological basis of these diseases, classification remains based on arbitrary symptomatic parameters. As a result, the existing pharmacological treatments have difficulties targeting relevant pathophysiological processes leading to high level of non-responding patients. Magnetic resonance spectroscopy (MRS) provides an outstanding means of measuring biochemical processes in vivo and can help identifying metabolic pathways that are associated with a given pathological condition. In this thesis, we have taken advantage of state-of-the-art MRS technologies at high field for studying metabolic dysfunctions associated with behavioral impairments in animal models of mood disorder. The overall goal consisted in finding potential biomarkers and endophenotypes (i.e. heritable biomarkers) with MRS, associate them with a molecular/physiological mechanism and evaluate the effect of a treatment targeting the observed dysfunction. We have successfully identified neuroenergetic abnormalities in different limbic regions of the brain in two mouse models of mood disorders; with a genetic or an environmental origin. Genetic deletion of an important metabolic regulator in mouse brain led to hippocampal neuroenergetic impairment and susceptibility to environmental stressors. Treating the animals with ebselen, an energy boosting mood stabilizer, allowed us to reduce the animal’s sensitivity to stress. With the same approach, we observed energy-related biomarkers associated with susceptibility to stress in the nucleus accumbens of genetically identical mice. We found that social hierarchy can predict the response to a chronic stressor and that behavioral impairments could be prevented by administering an energy stimulating compound, acetyl-L-carnitine. Finally, in an additional project, we have used MRS in an embryonic model in ovo to investigate for markers related to metabolic remodeling during neurogenesis. Our results support the idea that mood disorders arise from energy metabolism fragility in different regions of the limbic system with both environmental and genetic origin. Due to the high translational potential of MRS into clinics, our findings provide new biological targets or routes to study for a better understanding of mood disorders.

Neural stem cells (NSCs) are stem cells that with the ability of self-renew and multipledifferentiation potential. Under certain circumstances, NSCs are able to differentiate into neurons, astrocytes and oligodendrocytes, thereby participating in the neurogenesis and injury repair. The specific microenvironments regulating neural stem cells, commonly referred to as neurogenic niches, comprise multiple cell populations whose precise contributions are under active current exploration. Understanding the cross-talk between neural stem cells and their niche components is essential for the development of therapies against neurodegenerative disorders and spinal cord injury. In this review, we describe and discuss recent studies that identified novel components in the neural stem cell niche. These discoveries bring new concepts to the field. Therefore, we evaluate these recent advances that change our understanding of the neural stem cell niche and its influence on neural stem cell function. Key words: Neural stem cell; Niche; Nerve regeneration

Objective: Environmental enrichment (EE) or exercise can positively affect memory function through increased long-term potentiation and neurogenesis, which is facilitated by brain-derived neurotrophic factor (BDNF). BDNF promotes blood vessel growth, angiogenesis linked to adult neurogenesis, and neuronal survival. Here, we investigated the effects of EE, aerobic exercise, and their combination on plasma and hippocampal BDNF levels. Materials and Methods: Twenty-four 7-month-old adult male Wistar rats weighing 300–400 g were randomly assigned to the following four groups: control (C), aerobic exercise (A), EE, and combined EE and aerobic exercise (EEA). Interventions were given for 8 weeks, and plasma and hippocampal BDNF levels were measured using enzyme-linked immunosorbent assay. Results: A combination of aerobic exercise and continuous EE produced the largest increase in hippocampal and plasma BDNF levels in adult rats. A positive correlation (r = 0.686, P = 0.002, n = 24) was observed between plasma and hippocampal BDNF levels in adult rats. Conclusion: We conclude that a combination of aerobic exercise and continuous EE increases plasma and hippocampal BDNF in adult rats.

The elderly patients often suffered from cognitive decline. Chronic inflammatory responses inhibit hippocampal neurogenesis, which is one of the important mechanisms of cognitive decline in the elderly patients. To provide insights for further study and new thoughts for prevention or treatment of cognitive decline in elderly patients, this article reviewed the research progresses on regulation of peripheral and central inflammation to hippocampal neurogenesis and their role in cognitive decline in elderly patients. Key words: Inflammation; Hippocampal; Neurogenesis; Aged; Cognition

Traumatic brain injuries (TBIs) are a leading cause of death and disability. Additionally, growing evidence suggests a link between TBI-induced neuroinflammation and neurodegenerative disorders. Treatments for TBI patients are limited, largely focused on rehabilitation therapy, and ultimately, fail to provide long-term neuroprotective or neurorestorative benefits. Because of the prevalence of TBI and lack of viable treatments, new therapies are needed which can promote neurological recovery. Cell-based treatments are a promising avenue because of their potential to provide multiple therapeutic benefits. Cell-based therapies can promote neuroprotection via modulation of inflammation and promote neurorestoration via induction of angiogenesis and neurogenesis. Neural stem/progenitor cell transplantations have been investigated in preclinical TBI models for their ability to directly contribute to neuroregeneration, form neural-like cells, and improve recovery. Mesenchymal stem cells (MSCs) have been investigated in clinical trials through multiple different routes of administration. Intravenous administration of MSCs appears most promising, demonstrating a robust safety profile, correlation with neurological improvements, and reductions in systemic inflammation following TBI. While still preliminary, evidence suggests cell-based therapies may become a viable treatment for TBI based on their ability to promote neuroregeneration and reduce inflammation.

Weights and parameter bounds in the multi objective function. (PDF 751 kb)

Recent clinical studies report that children with multiple exposure to anesthesia are more likely to suffer from developing neurocognitive impairment, while single exposure to general anesthesia may not affect neurodevelopment. This article review clinical studies concerning repeated exposure to anesthetics on developing brain, which so far have not consistent results. Preclinical evidence indicates neurotoxicity due to repeated exposure to anesthetics, which may be related with neurogenesis, synaptic plasticity, and inflammatory reactions in the brain. The neurotoxicity of repeated exposure to anesthetics will become one of the hotspot in the research of anesthesia. Key words: Anesthetics; Developing brain; Repeated exposure

Cysteine modifications emerge as important players in cellular signaling and homeostasis. Here, we present a chemical proteomics strategy for quantitative analysis of reversibly modified Cysteines using bioorthogonal cleavable-linker and switch technique (Cys-BOOST). Compared to iodoTMT for total Cysteine analysis, Cys-BOOST shows a threefold higher sensitivity and considerably higher specificity and precision. Analyzing S-nitrosylation (SNO) in S-nitrosoglutathione (GSNO)-treated and non-treated HeLa extracts Cys-BOOST identifies 8,304 SNO sites on 3,632 proteins covering a wide dynamic range of the proteome. Consensus motifs of SNO sites with differential GSNO reactivity confirm the relevance of both acid-base catalysis and local hydrophobicity for NO targeting to particular Cysteines. Applying Cys-BOOST to SH-SY5Y cells, we identify 2,151 SNO sites under basal conditions and reveal significantly changed SNO levels as response to early nitrosative stress, involving neuro(axono)genesis, glutamatergic synaptic transmission, protein folding/translation, and DNA replication. Our work suggests SNO as a global regulator of protein function akin to phosphorylation and ubiquitination.

Here we demonstrate that not only is hippocampal neurogenesis persistent through the tenth decade of life, but it is detectable even in patients with mild cognitive impairments and Alzheimer’s disease. In a cohort of 18 patients with a mean age of 90.6 years, Nestin+Sox2+Ki67+ neural stem cells and DCX+ neuroblasts and immature neurons were detected, but their number greatly varies between patients. Nestin+ cells localize in the anterior hippocampus while neural progenitor cells, neuroblasts and immature neurons are evenly distributed along the entire anterior/posterior axis. Notably, the number of DCX+PCNA+ cells is reduced in mild cognitive impairments and higher numbers of neuroblasts are associated with better cognitive status. In addition, the number of DCX+PCNA+ cells correlate with the amount of presynaptic SNARE interactions. Our results suggest the existence of hippocampal neurogenesis in the aged and diseased human brain and the possible association of neurogenesis with cognition.

Objective To investigate whether (-)-epicatechin plays a role in neurological repair on traumatic brain injury in mice. Methods The mice model of traumatic brain injury was established by modified weight drop method. Experimental mice were randomly (random number) divided into the injury+ (Veh) group and the injury + (-)-epicatechin (EC) group. At 3 days after operation, the expression of IL-1β and TNF-α were detected. The number of necrotic cells of the lesion area was detected by PI staining. At 28 days after SCI, Morris Water Maze test was performed to observe the ability of spatial learning and memory in mice. The expression of neurotrophic factors BDNF and NGF were examined by qRT-PCR. The expression of NeuN was detected by immunofluorescence staining. EdU staining was used to observe the neurogenesis in the SGZ region. Results Compared with the Veh group, EC treated group showed better spatial learning and memory ability in time spent in correct quadrant at day 27 and 28 [24 d: (26.333±5.037)% vs (26.583±5.802)%, P=0.938; 25 d (33.300±4.724)% vs (29.767±3.347)%. P=0.166; 26 d: (41.017±7.246)% vs (32.800±8.145)%, P=0.095; 27 d: (48.017±7.424)% vs (35.267±6.748)%, P=0.011; 28 d: (51.617±9.017)% vs (41.116±6.467)%, P=0.043] and in latency to platform at day 27 and 28 [24 d: (62.967±5.494) s vs (63.917±7.027) s, P=0.800; 25 d: (50.533±10.305) s vs (57.217±13.085) s, P=0.349; 26 d: (40.333±10.526) s vs (50.133±11.039) s, P=0.147; 27 d: (28.717±4.137) s vs (44.533±7.181) s, P=0.001; 28 d: (21.950±6.889) s vs (37.567±5.974) s, P=0.002]. There was a decreased expression of IL-1β and TNF-α and increased level of neurotrophic factor BDNF and NGF after EC treatment in EC treatment group, compared to the veh treatment group [IL-1β and TNF-α: (42.690±3.057) ng/mL and (750.167±51.941) ng/mL vs (71.670±4.996) ng/mL and (1 085.167±68.535) ng/mL, P=0.000 6 and 0.003; BDNF and NGF: 0.543±0.033 and 0.334±0.041 vs 0.756±0.088 and 0.514±0.047, P=0.048 and 0.017)]. EC decreased the cell death near injury area (54.833±5.486 vs 74.000±5.323, P=0.031), increased NeuN positive cells (76.667±6.386 vs 42.167±5.237, P=0.002), and increased neurogenesis in SGZ area (12.667±0.760 vs 7.500±1.258, P=0.031). Conclusions (-)-Epicatechin plays an important role in functional recovery after traumatic brain injury in mice. The underlying mechanisms are closely related to inhibited inflammation, enhanced neurotrophic factors and improved neurogenesis. Key words: Traumatic brain injury; (-)-epicatechin; Nerve repair; Brain derived neurotrophic factor; Inflammation factors

The biological role of fibroblast growth factor-2 (FGF2) was extensive, previous researches confirmed FGF2 also effected on the neurogenesis and may be a new strategy for the treatment of neurological diseases. The study reviewed the research of FGF2 on the proliferation and differentiation of nervous system and treatment of neurological disease. Key words: Fibroblast growth factor-2; Neurogenesis; Neurological diseases

Objective To investigate the effects of umbilical cord blood neural stem cells (UCBNSCs) via stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling on neural recovery in rat models of intracerebral hemorrhage. Methods (1) In migration assay in vitro, UCBNSCs were distributed in the upper wells of Transwell plates, and SDF-1 at concentrations of 30, 60 and 120 ng/mL was placed in the lower wells. (2) Sixty rat models of intracerebral hemorrhage were randomly divided into UCBNSCs-transplanted group and phosphate buffer (PBS)-transplanted group (n=30); two d after modeling, 10 L UCBNSCs suspension and same amount of PBS were, respectively, transplanted into the two groups, and intraperitoneal injection of deoxyuridine (BrdU) labeled endogenous neural stem cells was performed; neurological functions were assessed with modified Neurological Severity Scale (mNSS) one d, and one and two weeks after cell transplantation; the expressions of SDF-1, vascular endothelial growth factor (VEGF), glial fibrillar acidic protein (GFAP), and doublecortin (DCX) were detected by immunofluorescence when the rats were sacrificed two weeks after cell transplantation; cell apoptosis was detected by TUNEL. Results (1) In the in vitro experiment, CXCR4 expression could be detected in UCBNSCs; 60 ng/mL SDF-1 had the greatest migration effect on UCBNSCs, and this effect showed statistically significant difference as compared with that at other concentrations (P<0.05). (2) In the in vivo experiment, two weeks after transplantation, the UCBNSCs-transplanted group had significantly increased number of BrdU-labeled cells in the subventricular zone, and significantly larger number of BrdU/DCX and BrdU/GFAP cells than the PBS-transplanted group (P<0.05); the VEGF expression in the brain injury area of the UCBNSCs-transplanted group ([88.30±7.21]/field) was significantly higher than that of PBS-transplanted group ([53.20±4.45]/field, t=4.144, P=0.000); the number of apoptotic cells in the brain injury area of the UCBNSCs-transplanted group ([34.30±2.44]/field) was significantly smaller than that of PBS-transplanted group ([47.70±1.98]/field, t=4.266, P=0.001); two weeks after transplantation, the mNSS scores of UCBNSCs-transplanted group (6.40±0.163) were significantly lower than those of the PBS-transplanted group (7.50±0.17, t=4.714, P=0.002). Conclusion SDF-1/CXCR4 can reach the injured area of cerebral hemorrhage after chemotactic transplantation of UCBNSCs and promote the recovery of nerve function in rats, whose mechanism may be that it can promote neurogenesis and VEGF secretion and inhibit apoptosis. Key words: Umbilical cord blood neural stem cell; Stromal cell-derived factor-1/CXC chemokine receptor 4; Intracerebral hemorrhage; Neurological damage

Objective To explore the effects of arsenic exposure on learning and memory and its potential mechanism in rats. Methods Water-based arsenic-exposed rat models were established on 4-10 postnatal days.The experimental animals were divided into 4 groups (10-12 cases in each group): the control group, the 15 μg/L As2O3 water group, the 30 μg/L As2O3 water group, and the 45 μg/L As2O3 water group.Cognitive functions were examined with the Morris water maze, exploratory behavior was detected by the exploratory behavior test.The hippocampus of pups from each experimental group was sectioned at various time points after arsenic exposure.The morphologies and neurogenesis of the neurons in the hippocampus CA1-CA3 region and dentate gyrus (DG) were observed by hematoxylin-eosin staining, Nissl staining, and doublecortin (DCX) immunostaining at different time points after arsenic exposure. Results Compared with the normal control group, the escape latency of the rats in the arsenic-exposed group was prolonged.The average escape latency of the rats in the normal control group, 15 μg/L As2O3 group, 30 μg/L As2O3 group and 45 μg/L As2O3 group were (17.00±9.53) s, (35.89±19.81) s, (26.60±18.84) s, and (33.79±18.08) s, respectively, and the difference among 4 groups was statistically significant (F=3.591, P<0.05), and the residence time in the original target quadrant was shortened, respectively, (38.93±8.33) s, (36.03±16.25) s, (29.85±9.27) s, and (29.84±10.16) s, respectively, and there was no significant difference among 4 groups (F=1.681, P=0.187). HE staining and Nissl staining showed that pathological changes such as edema, degeneration and necrosis were observed in the hippocampal CA1 area and CA2 area as well as dentate gyrus cells in rats exposed to arsenic in the acute phase.The higher the concentration of arsenic exposure, the more obvious the cell structure disorder was.However, 5 weeks after exposure, the pathological changes in hippocampal neurons in the arsenic-exposed group gradually returned to normal.Immunohistochemistry showed that the expressions of DCX in the CA1, CA2 and dentate gyrus of rats exposed to arsenic decreased significantly 24 h after arsenic exposure, especially in the 45 μg/L group.Five weeks after arsenic exposure, there was no expression in the hippocampal CA1-CA3 area, and there was still a small amount of expression in the dentate gyrus. Conclusions Postnatal low-concentration arsenic exposure may impair learning and abnormal germination of neurons in the hippocampal dentate gyrus may be the underlying mechanism. Key words: Arsenic exposure; Learning and memory; Hippocampus; Mechanism

Objective To investigate whether mild hypothermia can promote neurogenesis in the dentate gyrus of hippocampus and cognitive function recovery after traumatic brain injury (TBI) through inhibiting apoptosis of hippocampal neurons. Methods A total of 66 healthy adult Sprague-Dawley rats were randomly divided into sham group, TBI group and TBI+ hypothermia group, with 22 rats in each group. The rat TBI model was established using the fluid percussion device. The rats in TBI+ hypothermia group received 4-hour hypothermia therapy immediately after injury, with the target temperature of 33.5℃. Bromodeoxyuridine (BrdU) was injected into the rats' abdominal cavity to label the mitotic cells. The test of Morris water maze was used to evaluate the rats' spatial learning and memory capabilities. Immunofluorescence staining was used to observe the expression levels of BrdU, doublecortin (DCX), neuron specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3) and cleaved caspase-3 expressions in dentate gyrus of hippocampus at 7 days and 28 days after injury. Expressions apoptosis-related proteins including the factor associated suicide (FAS)/factor associated suicide ligand (FASL), B-cell lymphoma-2 (Bcl-2), caspase-3 and cleaved caspase-3 expressions were detected by Western blot assay. Results The water maze tests at 28 days after injury showed that compared with TBI group, the escape latency in TBI+ hypothermia group was significantly shorter [(24.2±5.9)s∶(18±4.1)s], and both the time in the target quadrant and the number of platform crossing were increased significantly [(24.9±6.5)s∶(31.7±5.2)s; (1.9±0.8) times∶(3.5±1.2)times](P<0.05). Compared with the sham group, in TBI group and TBI+ hypothermia group, the BrdU+ new-born cells in the dentate gyrus of hippocampus were significantly increased at 7 days after injury [(9.4±4.1)∶(33.4±3.8); (9.4±4.1)∶(45.8±5.6)], the BrdU+ /DCX+ new-born neurons were increased at 7 days after injury [(2.0±0.6)∶(9.6±1.6); (2.0±0.6)∶(19.2±3.7)], and the BrdU+ /NeuN+ mature neurons were increased at 28 days after injury [(2.6±1.0)∶(17.2±3.9); (2.6±1.0)∶(33.6±9.1)] (P<0.01). TBI group showed more obvious increase than the TBI+ hypothermia group (P<0.01). Moreover, compared with 7 days after injury, the number of BrdU+ cells at 28 days after injury was further increased in TBI+ hypothermia group but decreased in TBI group [(45.8±5.6)∶(58.8±9.2); (33.4±3.8)∶(22.0±3.5)](P<0.05 or <0.01). Compared with the sham group, the caspase-3+ NeuN+ and caspase-3+ NeuN+ apoptotic neurons were significantly increased at 7 days after injury in TBI group [(2.0±0.9)∶(11.6±2.6); (2.6±1.0)∶(10.2±2.9)] (P<0.05). Compared with the TBI group, the cleaved caspase-3+ NeuN+ apoptotic neurons were decreased in TBI+ hypothermia group [(6.6±2.0)∶(11.6±2.6)](P<0.05). Furthermore, compared with the TBI group, mild hypothermia might down-regulate the expression of FAS, FASL, cleaved caspase-3 and caspase-3 and up-regulate the expression of Bcl-2 in the hippocampus [(1.54±0.15) ∶(1.14±0.12); (1.06±0.04)∶(0.80±0.09); (0.84±0.03)∶(0.62±0.08); (0.93±0.06)∶(0.86±0.09); (0.71±0.01)∶(1.58±0.18)](P<0.05). Conclusions Mild hypothermia might inhibit apoptosis of hippocampal neurons through cleaved caspase-3, FAS/FASL and Bcl-2 pathways, thus improving the neurogenesis and maturation of neurons in the dentate gyrus of hippocampus and facilitating cognitive function recovery in rats. It indicates that the function of hypothermia in anti-apoptosis and neurogenesis and maturity of hippocampal neurons may have a potential role in predicting the prognosis of TBI patients. Key words: Hypothermia; Brain injuries; Hippocampus; Neuve regeneration; Apoptosis