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

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

Exploring adult hippocampal neurogenesis using optogenetics

In the 1980s, it was widely accepted that new neurons are continuously generated in the dentate gyrus of the mammalian hippocampus. Since its acceptance, researchers have employed various techniques and behavioral paradigms to study the proliferation, differentiation, and functional role of adult-born neurons. This literature thesis aims to discuss how optogenetics is able to overcome the limitations of past techniques and provide the field with new insights into the functional role of neurogenesis. We will review the current knowledge on both adult hippocampal neurogenesis and optogenetics, present representative studies using optogenetics to investigate neurogenesis and discuss potential limitations and concerns involved in using optogenetics

Neurogenesis and astrogenesis contribute to vestibular compensation in the neurectomized adult cat: cellular and behavioral evidence

Neurogenesis occurs in some regions of the adult mammalian brain and gives rise to neurons integrated into functional networks. In pathological or postlesional conditions, neurogenesis and astrogenesis can also occur, as demonstrated in the deafferented vestibular nuclei after unilateral vestibular neurectomy in the adult cat. Here we report that in cats infused with an antimitotic drug, cytosine-[beta]-D arabinofuranoside (AraC), the number of GAD67 and GFAP immunoreactive cells is increased, despite the total mitotic activity blockade observed in the deafferented vestibular nuclei after unilateral vestibular neurectomy. At the behavioral level, recovery of posturo-locomotor function was drastically delayed, and no alteration of the horizontal spontaneous nystagmus was observed. These cellular and behavioral results suggest that reactive neurogenesis and astrogenesis might contribute highly to vestibular compensation in the adult cat, probably by accelerating the recovery of vestibular functions

Reduction of adult hippocampal neurogenesis modifies brain functional connectivity and enhances cocaine-seeking in mice

Recently, adult hippocampal neurogenesis has been proposed as a putative neuroplastic mechanism involved in those behavioural processes. In this work, we studied the effect of the inhibition of adult hippocampal neurogenesis using the DNA alkylating agent temozolomide (TMZ), in cocaine-induced conditioned place preference (CPP) behaviour. In a first experiment, we investigated both CPP acquisition/expression and the functional brain circuits underlying CPP expression in control and neurogenesis-reduced conditions by analysing c-Fos immunoreactivity (c-Fos IR) in hippocampal and extrahippocampal addiction-related areas. A second experiment was designed to study the involvement of adult-born neurons in the extinction and cocaine-induced reinstatement of drug-seeking in the CPP model. We performed two independent studies where adult hippocampal neurogenesis was inhibited either before or after the CPP was acquired. Our results showed that TMZ treatment had no effect on the acquisition of the cocaine-induced CPP, but c-Fos IR associated to the test trial (CPP expression) revealed an increased activity in some of the analysed brain areas in the CPP-TMZ mice. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain network associated with CPP expression. However, mice with reduced neurogenesis showed an alternative brain circuit. The results of the second experiment revealed that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug seeking behaviour. However, when neurogenesis was inhibited after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that the role of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition.Universidad de Málaga. Andalucía Tech, Campus de Excelencia Internacional. Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to L.J.S.; Subprograma RETICS Red de Trastornos Adictivos RD12/0028/0001, to F.R.F.). Author E.C-O. holds a ‘Sara Borrell’ research contract from the Spanish Carlos III Health Institute, Spanish Ministry of Economy and Competitiviness (grant number CD12/00455). Author D.L.G-M. holds a ‘FPU’ grant from the Spanish Ministry of Education, Culture and Sports (grant number FPU13/04819)

The systemic environment: at the interface of aging and adult neurogenesis.

Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms

Adult neurogenesis, mental health, and mental illness: hope or hype?

Psychiatric and neurologic disorders take an enormous toll on society. Alleviating the devastating symptoms and consequences of neuropsychiatric disorders such as addiction, depression, epilepsy, and schizophrenia is a main force driving clinical and basic researchers alike. By elucidating these disease neuromechanisms, researchers hope to better define treatments and preventive therapies. Research suggests that regulation of adult hippocampal neurogenesis represents a promising approach to treating and perhaps preventing mental illness. Here we appraise the role of adult hippocampal neurogenesis in major psychiatric and neurologic disorders within the essential framework of recent progress made in understanding "normal" adult neurogenesis. Topics addressed include the following: the life cycle of an adult hippocampal stem cell and the implications for aging; links between learning and hippocampal neurogenesis; the reciprocal relationship between cocaine self-administration and adult hippocampal neurogenesis; the role of adult neurogenesis in an animal model of depression and response to antidepressant exposure; the impact of neonatal seizures on dentate gyrus neurogenesis; and the contribution of a schizophrenia-susceptibility gene to adult hippocampal neurogenesis. These topics are discussed in light of the regulation of adult neurogenesis, the relationship to normal neurogenesis in adulthood and aging, and, importantly, the manipulation of neurogenesis to promote mental health and treat mental illness