Regulation and function of adult neurogenesis: from genes to cognition.

Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.

Enrichment rescues contextual discrimination deficit associated with immediate shock.

Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis.

Students' perceptions of social issues in biology courses.

Students' scientific literacy may be improved by the integration of social issues into biology courses, enabling them to make informed decisions on social issues in the context of their scientific knowledge. Additionally, this may allow students to recognize the connection between science and society. Although there are a number of benefits with having students learn about social issues in biology courses, most undergraduate courses may follow a traditional curriculum, which emphasizes the scientific content without framing it in a social context. Here, we investigated whether undergraduate students have been exposed to social issues in previous biology courses and examined how their perceptions changed before and after taking a biology course that incorporated social issues. In surveys, most students reported having no exposure to social issues in biology courses. Most students, especially females and persons excluded because of their ethnicity or race (PEERs), agreed with the integration of social issues in biology courses before taking the course. Students found reflection essays to be a useful tool in allowing them to think and share their thoughts on social issues as well as relate the course content to their personal lives. These results highlight students' interest in learning about social issues from a scientific perspective and how reflection essays may be used to practice applying their knowledge to real-world issues.

PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness.

The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused an ∼50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.

Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation.

Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein-1 (MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children.

Students Need More than Content Knowledge To Counter Vaccine Hesitancy.

To better prepare undergraduate students as informed citizens, they need skills to evaluate and interpret scientific data that are relevant to real world scenarios. Socioscientific issues are typically complicated or debatable issues that require individuals to evaluate their background knowledge and make decisions with respect to social and cultural contexts. Incorporation of socioscientific issues into a course allows students opportunities to demonstrate their argumentation skills. In this study, we investigated the relationship between students' biological content knowledge and their argumentation skills. We evaluated students' content knowledge of primary research articles on mRNA vaccine development and clinical trials. There was no correlation of content knowledge and students' argumentation skills to counter vaccine hesitancy. While most students demonstrated understanding of the primary research articles, almost half the students did not include specific biological knowledge in their arguments, indicating they had difficulty in applying their knowledge to the real world. These results suggest there is a need to provide students with additional opportunities to practice and develop their argumentation skills with respect to socioscientific issues.

Mitochondrial protection attenuates inflammation-induced impairment of neurogenesis in vitro and in vivo.

The impairment of hippocampal neurogenesis has been linked to the pathogenesis of neurological disorders from chronic neurodegenerative disease to the progressive cognitive impairment of children who receive brain irradiation. Numerous studies provide evidence that inflammation downregulates neurogenesis, with multiple factors contributing to this impairment. Although mitochondria are one of the primary targets of inflammatory injury, the role of mitochondrial function in the modulation of neurogenesis remains relatively unstudied. In this study, we used neurosphere-derived cells to show that immature doublecortin (Dcx)-positive neurons are uniquely sensitive to mitochondrial inhibition, demonstrating rapid loss of mitochondrial potential and cell viability compared with glial cells and more mature neurons. Mitochondrial inhibition for 24 h produced no significant changes in astrocyte or oligodendrocyte viability, but reduced viability of mature neurons by 30%, and reduced survival of Dcx(+) cells by 60%. We demonstrate that protection of mitochondrial function with mitochondrial metabolites or the mitochondrial chaperone mtHsp75/mortalin partially reverses the inflammation-associated impairment of neurogenesis in vitro and in irradiated mice in vivo. Our findings highlight mitochondrial mechanisms involved in neurogenesis and indicate mitochondria as a potential target for protective strategies to prevent the impairment of neurogenesis by inflammation.

The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain.

BACKGROUND AND PURPOSE: The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia. METHODS: Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2-/- reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test. RESULTS: Using NSC isolated from CCR2+/+ and CCR2-/- mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2-/- mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2-/- cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2-/- NSC. CONCLUSIONS: The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.

Does the Match between Gender and Race of Graduate Teaching Assistants and Undergraduates Improve Student Performance in Introductory Biology?

Research suggests there are potential benefits to students when taught by instructors who share the same gender and/or race/ethnicity. While underrepresented students have shown increased persistence and academic performance when they were taught by gender- and/or race/ethnicity-congruent faculty, there is little research that has explored the influence of matching for graduate student teaching assistants (GTAs). Given that science, technology, engineering, and mathematics (STEM) GTAs spend a significant amount of time with undergraduates, measurable impacts on student outcomes have the potential to contribute to the success of undergraduates who have been underrepresented in STEM fields. This study evaluated the effects on academic performance of GTA (n = 50) matching for first-year students (n = 976) in an introductory biology lab course at a Hispanic-serving institution. There was no significant difference in academic performance for students who matched with the gender, race/ethnicity, income, and first-generation status of their GTAs. Results were consistent across multiple cohorts of students, after including statistical controls for prior academic performance and other demographic characteristics and accounting for the nested structure of the data. These results suggest there is a need of supporting GTAs to develop more effective teaching practices and to consider effects of GTA matching on other outcomes.

The Impact of a Pedagogy Course on the Teaching Beliefs of Inexperienced Graduate Teaching Assistants.

There has been little attention given to teaching beliefs of graduate teaching assistants (GTAs), even though they represent the primary teaching workforce for undergraduate students in discussion and laboratory sections at many research universities. Secondary school education studies have shown that teaching beliefs are malleable and can be shaped by professional development, particularly for inexperienced teachers. This study characterized inexperienced GTAs' teaching beliefs about student learning and how they change with a science-specific pedagogy course that emphasized student learning. GTA teaching beliefs were characterized as traditional (providing information to students), instructive (providing activities for students), and transitional (focusing on student-teacher relationships). At the start of the course, traditional, instructive, and transitional beliefs were emphasized comparably in the concept maps and presentations of inexperienced GTAs. At the end of the course, although GTAs' beliefs remained mostly teacher focused, they were more instructive than traditional or transitional. GTAs included teaching strategies and jargon from the course in their concept maps but provided minimal explanations about how opportunities for active student engagement would impact student learning. These results suggest there is a need to provide ongoing discipline-specific professional development to inexperienced GTAs as they develop and strengthen their teaching beliefs about student learning.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

NMDA receptors mediate feeding elicited by neuropeptide Y in the lateral and perifornical hypothalamus.

Neuropeptide Y (NPY) and N-methyl-d-aspartate (NMDA) receptors in the lateral (LH) and perifornical hypothalamus (PFH) are believed to be involved in the stimulation of feeding behavior. To investigate the possibility that neurons with these receptors interact to stimulate eating, the NMDA receptor antagonists d-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) or 7-chlorokynurenic acid (7-CK) were injected into the LH or PFH of satiated rats 5 min prior to NPY in the same site and subsequent food intake was measured 1, 2, and 4 h postinjection. The injection of NPY (78 pmol/0.3 microl aCSF) in the PFH produced an average food intake of 9.7 g in 4 h, compared to the intake of 1.3 g after the artificial cerebrospinal fluid (aCSF) vehicle. D-AP5 (1, 10, or 20 nmol/0.3 microl aCSF) pretreatment suppressed NPY-induced eating, with the 20 nmol dose of D-AP5 producing up to an 80% suppression of elicited food intake down to 1.9 g in 4 h. Similar effects were produced with the LH as the injection site. Illustrating the specificity of the NMDA receptor antagonist's suppression of NPY-elicited feeding, D-AP5 suppressed NMDA-elicited feeding but did not affect the eating response induced by kainic acid. Consistent with the effects of D-AP5, the NMDA receptor antagonist 7-CK (40 nmol/0.3 microl dimethyl sulfoxide, DMSO) suppressed feeding elicited by NPY in the LH by 78%. Collectively, the findings suggest that the feeding elicited by NPY is dependent upon the activation of the NMDA receptors in the LH and PFH.

PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06.

PURPOSE: The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model. PROCEDURES: Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography. RESULTS: [(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET. CONCLUSIONS: [(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

Resistance to genotoxic stresses in Arctica islandica, the longest living noncolonial animal: is extreme longevity associated with a multistress resistance phenotype?

Bivalve molluscs are newly discovered models of successful aging. Here, we test the hypothesis that extremely long-lived bivalves are not uniquely resistant to oxidative stressors (eg, tert-butyl hydroperoxide, as demonstrated in previous studies) but exhibit a multistress resistance phenotype. We contrasted resistance (in terms of organismal mortality) to genotoxic stresses (including topoisomerase inhibitors, agents that cross-link DNA or impair genomic integrity through DNA alkylation or methylation) and to mitochondrial oxidative stressors in three bivalve mollusc species with dramatically differing life spans: Arctica islandica (ocean quahog), Mercenaria mercenaria (northern quahog), and the Atlantic bay scallop, Argopecten irradians irradians (maximum species life spans: >500, >100, and ~2 years, respectively). With all stressors, the short-lived A i irradians were significantly less resistant than the two longer lived species. Arctica islandica were consistently more resistant than M mercenaria to mortality induced by oxidative stressors as well as DNA methylating agent nitrogen mustard and the DNA alkylating agent methyl methanesulfonate. The same trend was not observed for genotoxic agents that act through cross-linking DNA. In contrast, M mercenaria tended to be more resistant to epirubicin and genotoxic stressors, which cause DNA damage by inhibiting topoisomerases. To our knowledge, this is the first study comparing resistance to genotoxic stressors in bivalve mollusc species with disparate longevities. In line with previous studies of comparative stress resistance and longevity, our data extends, at least in part, the evidence for the hypothesis that an association exists between longevity and a general resistance to multiplex stressors, not solely oxidative stress. This work also provides justification for further investigation into the interspecies differences in stress response signatures induced by a diverse array of stressors in short-lived and long-lived bivalves, including pharmacological agents that elicit endoplasmic reticulum stress and cellular stress caused by activation of innate immunity.

New neurons in an aged brain.

Adult hippocampal neurogenesis is one of the most robust forms of synaptic plasticity in the nervous system and occurs throughout life. However, the rate of neurogenesis declines dramatically with age. Older animals have significantly less neural progenitor cell proliferation, neuronal differentiation, and newborn neuron survival compared to younger animals. Intrinsic properties of neural progenitor cells, such as gene transcription and telomerase activity, change with age, which may contribute to the observed decline in neurogenesis. In addition, age-related changes in the local cells of the neurogenic niche may no longer provide neural progenitor cells with the cell-cell contact and soluble cues necessary for hippocampal neurogenesis. Astrocytes, microglia, and endothelial cells undergo changes in morphology and signaling properties with age, altering the foundation of the neurogenic niche. While most studies indicate a correlation between decreased hippocampal neurogenesis and impaired performance in hippocampus-dependent cognitive tasks in aged mice, a few have demonstrated that young and aged mice are equivalent in their cognitive ability. Here, we summarize the different behavioral paradigms to test hippocampus-dependent cognition and the need to develop neurogenesis-dependent tasks.

MHC mismatch inhibits neurogenesis and neuron maturation in stem cell allografts.

BACKGROUND: The role of histocompatibility and immune recognition in stem cell transplant therapy has been controversial, with many reports arguing that undifferentiated stem cells are protected from immune recognition due to the absence of major histocompatibility complex (MHC) markers. This argument is even more persuasive in transplantation into the central nervous system (CNS) where the graft rejection response is minimal. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluate graft survival and neuron production in perfectly matched vs. strongly mismatched neural stem cells transplanted into the hippocampus in mice. Although allogeneic cells survive, we observe that MHC-mismatch decreases surviving cell numbers and strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. Immune suppression with cyclosporine-A did not improve outcome but non-steroidal anti-inflammatory drugs, indomethacin or rosiglitazone, were able to restore allogeneic neuron production, integration and retention to the level of syngeneic grafts. CONCLUSIONS/SIGNIFICANCE: These results suggest an important but unsuspected role for innate, rather than adaptive, immunity in the survival and function of MHC-mismatched cellular grafts in the CNS.

Signaling in adult neurogenesis.

Neural stem cells (NSCs) in the adult brain continuously supply new neurons to the hippocampal dentate gyrus (DG) and the olfactory bulb (OB). Recent studies indicate that the progression from neural precursor cells (NPCs) to mature neurons is tightly controlled by coordinate cell-intrinsic programs and external signals within the neurogenic niche. In this review, we summarize both classes of regulatory factors involved in distinct stages of adult neurogenesis, including proliferation and lineage differentiation of NSCs, migration of neuroblasts and integration of newborn neurons. A full understanding of the wide variety of signaling pathways will ultimately provide precise targets for therapeutic applications.