Erythropoietin promotes hippocampal mitochondrial function and enhances cognition in mice

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.

Longitudinal developmental trajectories do not follow cross-sectional age associations in hippocampal subfield and memory development

Many cross-sectional findings suggest that volumes of specific hippocampal subfields increase in middle childhood and early adolescence. In contrast, a small number of available longitudinal studies observed decreased volumes in most subfields over this age range. Further, it remains unknown whether structural changes in development are associated with corresponding gains in children's memory. Here we report cross-sectional age differences in children's hippocampal subfield volumes together with longitudinal developmental trajectories and their relationships with memory performance. In two waves, 109 healthy participants aged 6 to 10 years (wave 1: M=7.25 years, wave 2: M=9.27 years) underwent high-resolution magnetic resonance imaging to assess hippocampal subfield volumes, and completed cognitive tasks assessing hippocampus dependent memory processes. We found that cross-sectional age-associations and longitudinal developmental trends in hippocampal subfield volumes were highly discrepant, both by subfields and in direction. Further, volumetric changes were largely unrelated to changes in memory, with the exception that increase in subiculum volume was associated with gains in spatial memory. Importantly, the observed longitudinal patterns of brain-cognition coupling could not be inferred from cross-sectional findings. We discuss potential sources of these discrepancies. This study underscores that children's structural brain development and its relationship to cognition cannot be inferred from cross-sectional age comparisons.

SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice

Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.

Age-associated gut microbiota impairs hippocampus-dependent memory in a vagus-dependent manner

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment are not yet elucidated. Here we show that the colonization of mice with the gut microbiota from aged, but not young animals is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampal-dependent memory. Similar alterations were reported in mice following the transfer of microbiota from aged human healthy donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain functioning, we mapped the neuronal activity patterns and report that aged-microbiota transplantation reduced neuronal activity upstream to the vagus nerve. Targeted pharmacogenetic manipulation of the ascending branch of the vagus nerve demonstrated that the mere decrease in vagal activity was also detrimental to hippocampal functions. In contrast, increasing vagal activity alleviated the adverse effects of age-associated microbiota transfer on hippocampal functions and reinstated normal hippocampal memory in aged mice. We conclude that vagus nerve stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.Graphical abstract

Genetic depletion of BDNF impairs both context-dependent and context-independent extinction learning of a spatial appetitive task

Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent learning, as well as hippocampus-dependent learning. Extinction learning (EL) comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. Concordantly, the participation of BDNF in hippocampus-dependent memory is experience-dependent. BDNF has been associated with synaptic plasticity needed for acquisition and extinction learning of fear conditioning. However, little is known about its influence on the extinction and renewal of spatial appetitive extinction learning (EL). In this study, in BDNF+/−-mice we evaluated to what extent BDNF contributes to spatial appetitive EL in the presence (ABA) or absence (AAA) of a context change. Daily training, to reach acquisition criterion in a T-maze, resulted in a similar outcome in BDNF+/−-mice or their wildtype (wt) littermates. EL was delayed in the AAA, and significantly impaired in the ABA-context compared to EL in wt littermates. When renewal was tested in the ABA paradigm we detected a significant response in wt controls, but not in BDNF+/−-mice. Taken together, these results support an important role for BDNF in EL in AAA and ABA context, as well as renewal of a spatial appetitive task, processes that relate to information updating and retrieval.

Inducible and Conditional Stimulation of Adult Hippocampal Neurogenesis Rescues Cadmium-Induced Impairments of Adult Hippocampal Neurogenesis and Hippocampus-Dependent Memory in Mice

Cadmium (Cd) is a heavy metal and an environmental pollutant. However, the full spectrum of its neurotoxicity and the underlying mechanisms are not completely understood. Our previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. This study aims to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, we utilized the transgenic constitutive active MEK5 (caMEK5) mouse strain we previously developed and characterized. This mouse strain enables us to genetically and conditionally activate adult neurogenesis by administering tamoxifen to induce expression of a caMEK5 in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous extracellular signal-regulated kinase 5 mitogen-activated protein kinase pathway. The caMEK5 mice were exposed to 0.6 mg/l Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. We report here that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory.

Manipulating neural activity and sleep-dependent memory consolidation

Sleep contributes actively to the consolidation of many forms of memory. This review describes the neural oscillations of non-rapid eye movement (NREM) sleep, the structures underlying these oscillations and their relation to hippocampus-dependent memory consolidation. A main focus lies on the relation between inter- and intraregional interactions and their electrophysiological representation. Methods for modulating neural oscillations with the intent of affecting memory consolidation are presented.