A Standardized Protocol for Stereotaxic Intrahippocampal Administration of Kainic Acid Combined with Electroencephalographic Seizure Monitoring in Mice

Lack of scientific reproducibility is a growing concern and weak experimental practices may contribute to irreproducibility. Here, we describe an optimized and versatile protocol for stereotaxic intrahippocampal administration of Kainic Acid (KA) in mice with a C57Bl6 background. In this protocol, KA administration is combined with in vivo recording of neuronal activity with wired and wireless setups. Following our protocol, KA administration results in a robust dose-dependent induction of low-level epileptiform activity or Status Epilepticus (SE) and induces previously characterized hallmarks of seizure-associated pathology. The procedure consists of three main steps: Craniotomy, stereotaxic administration of KA, and placement of recording electrodes in intrahippocampal, and subdural locations. This protocol offers extended possibilities compared to the systemic administration of KA, as it allows the researcher to accurately regulate the local dose of KA and resulting seizure activity, and permits the use and study of convulsive and non-convulsive KA doses, resulting in higher reproducibility and lower inter-individual variability and mortality rates. Caution should be taken when translating this procedure to different strains of mice as inter-strain sensitivity to KA has been described before. The procedure can be performed in ~1 h by a trained researcher, while intrahippocampal administration of KA without placing recording electrodes can be done in 25 min, and can be easily adapted to the titrated intrahippocampal administration of other drugs

Optical suppression of tilt-to-length coupling in the LISA long-arm interferometer

The arm length and the isolation in space enable the Laser Interferometer Space Antenna (LISA) to probe for signals unattainable on the ground, opening a window to the subhertz gravitational-wave universe. The coupling of unavoidable angular spacecraft jitter into the longitudinal displacement measurement, an effect known as tilt-to-length (TTL) coupling, is critical for realizing the required sensitivity of picometer / √ Hz . An ultrastable interferometer test bed has been developed in order to investigate this issue and validate mitigation strategies in a setup representative of LISA and in this paper it is operated in the long-arm interferometer configuration. The test bed is fitted with a flat-top beam generator to simulate the beam received by a LISA spacecraft. We demonstrate a reduction of TTL coupling between this flat-top beam and a Gaussian reference beam via the introduction of two- and four-lens imaging systems. TTL coupling factors below ± 25 μ m / rad for beam tilts within ± 300 μ rad are obtained by careful optimization of the system. Moreover, we show that the additional TTL coupling due to lateral-alignment errors of elements of the imaging system can be compensated by introducing lateral shifts of the detector and vice versa. These findings help validate the suitability of this noise-reduction technique for the LISA long-arm interferometer

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain

Gene regulation in adult neural stem cells:Current challenges and possible applications

Adult neural stem and progenitor cells (NSPCs) offer a unique opportunity for neural regeneration and niche modification in physiopathological conditions, harnessing the capability to modify from neuronal circuits to glial scar. Findings exposing the vast plasticity and potential of NSPCs have accumulated over the past years and we currently know that adult NSPCs can naturally give rise not only to neurons but also to astrocytes and reactive astrocytes, and eventually to oligodendrocytes through genetic manipulation. We can consider NSPCs as endogenous flexible tools to fight against neurodegenerative and neurological disorders and aging. In addition, NSPCs can be considered as active agents contributing to chronic brain alterations and as relevant cell populations to be preserved, so that their main function, neurogenesis, is not lost in damage or disease. Altogether we believe that learning to manipulate NSPC is essential to prevent, ameliorate or restore some of the cognitive deficits associated with brain disease and injury, and therefore should be considered as target for future therapeutic strategies. The first step to accomplish this goal is to target them specifically, by unveiling and understanding their unique markers and signaling pathways

Adult Neurogenesis, Chronic Stress and Depression

A major risk factor for depression in vulnerable individuals is exposure to stress during critical periods. Stress affects mood and cognition and is also one of the best known inhibitors of adult neurogenesis that has been associated with hippocampal changes and atrophy, common findings in major depression (models). While the effects of acute or mild stress are generally short-lived and recover quickly, chronic and severe stress can induce longer lasting reductions in neurogenesis that, depending on the age of exposure, can affect hippocampal structure and function, alter hippocampal plasticity, and increase vulnerability to psychopathology. Stress-induced reductions in neurogenesis can in part be normalized by positive stimuli for plasticity such as exercise, by drugs targeting the stress system, and by some, but not all, antidepressants. Exposure to stress during sensitive periods of (early) life increases the risk for developing cognitive or anxiety symptoms, common to many brain diseases, including depression. Recruiting the plasticity still present in the adult brain, e.g., through normalization of neurogenesis, may be required for a successful treatment response and recovery