K. V. Anokhin

Towards a new developmental synthesis: adaptive developmental plasticity and human disease

1focusing mainly on short-term outcomes such as infant survival and stunting. 2 However, the longer term eff ects on adult health 3 of a poor start to life suggest a further perspective. Developmental eff ects have been viewed traditionally in the context of major disruptions such as caused by teratogens, prematurity and growth retardation, but there is increasing appreciation of the role of developmental plasticity, which provides individuals with the fl exibility to adjust their trajectory of development to match their environment. Plasticity operates across the entire range of environment, from undernutrition to excessive nutritional environments associated with gestational diabetes or maternal obesity, 4,5

Reminder effects - reconsolidation or retrieval deficit? Pharmacological dissection with protein synthesis inhibitors following reminder for a passive-avoidance task in young chicks

It is generally accepted that memory formation involves an irreversible passage via labile phases to the stable form of ‘long‐term memory’ impervious to amnestic agents such as protein synthesis inhibitors. However, recent experiments demonstrate that reactivation of memory by way of a reminder renders it labile to such inhibitors, suggesting that such retrieval is followed by a so‐called reconsolidation process similar or identical in its cellular and molecular correlates to that occurring during the initial consolidation. We compared the effects of the protein synthesis inhibitor anisomycin and the glycoprotein synthesis inhibitor 2‐deoxygalactose on the temporal dynamics and pharmacological sensitivity of initial consolidation and memory expression following a reminder in a one‐trial passive‐avoidance task in day‐old chicks. This comparison revealed three differences between the action of the inhibitors on newly formed compared with reactivated memory. First, the recall deficit after the reminder was temporary, whilst the amnesia following inhibitor treatment during training was stable. Second, the sensitive period for the effect of anisomycin was shorter in the reminder than in the training situation. Third, the effective dose for either inhibitor for reminder‐associated amnesia was several times lower than for amnesia developing after training. Thus though like initial consolidation, memory expression at delayed periods following reminder depends on protein and glycoprotein synthesis, the differences between the temporal and pharmacological dynamics in the two situations point to the distinct character of the molecular processes involved in postreminder effects.

Mechanisms of memory reorganization during retrieval of acquired behavioral experience in chicks: the effects of protein synthesis inhibition in the brain.

According to current concepts, memory can be disrupted by administration of protein synthesis inhibitors over a relatively short time period before and after learning. However, data have been obtained indicating that protein synthesis inhibitors can induce amnesia when given long after learning if administration is performed in reminder conditions, i.e., when the animal is presented with one of the environmental components which previously formed the learning situation. The aim of the present work was to confirm the possibility of inducing memory disruption in chicks at late post–learning stages by administering the protein synthesis inhibitor cycloheximide in association with a reminder procedure. Day–old chicks were trained to perform a standard passive avoidance task. Chicks were given cycloheximide (20 μg, intracerebrally) 5 min before the reminder procedure, which was performed 2, 24, or 48 h after training. Testing was conducted 0.5, 1, 3, 24, and 48 h after the reminder. Administration of cycloheximide in association with the reminder procedure induced the development of temporary amnesia, whose duration gradually decreased as the interval between training and reminding increased. These data led to the hypothesis that a memory reactivated by a reminder undergoes a process of reorganization and reconsolidation, which depends on the synthesis of new proteins. The quenching of the ability of protein synthesis inhibition during the reminder to disrupt memory demonstrates the existence of a gradual process resulting in consolidation of memory between 2 and 48 h of learning.

Antisense oligodeoxynucleotides to c-fos are amnestic for passive avoidance in the chick

Induction of c-fos occurs in the forebrain when chicks are trained on a passive avoidance task. Suppression of c-Fos protein synthesis with antisense oligodeoxynucleotides prevented long-term memory retention when injected 10-11 h before training, but not if injections were made between 3 h pre-and 3 h post-training. c-fos expression is thus necessary for long-term memory retention, presumably because of its control of induction of the signalling pathway that ultimately results in the protein synthesis subserving synaptic remodelling.

Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth

During inner ear development programmed cell death occurs in specific areas of the otic epithelium but the significance of it and the molecules involved have remained unclear. We undertook an analysis of mouse mutants in which genes encoding apoptosis-associated molecules have been inactivated. Disruption of the Apaf1 gene led to a dramatic decrease in apoptosis in the inner ear epithelium, severe morphogenetic defects and a significant size reduction of the membranous labyrinth, demonstrating that an Apaf1-dependent apoptotic pathway is necessary for normal inner ear development. This pathway most probably operates through the apoptosome complex because caspase 9 mutant mice suffered similar defects. Inactivation of the Bcl2-like (Bcl2l) gene led to an overall increase in the number of cells undergoing apoptosis but did not cause any major morphogenetic defects. In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development. In Apaf1-/-/Bcl2l-/- double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-XL in the otic epithelium is Apaf1-dependent. Furthermore, the otic vesicle failed to close completely in all double mutant embryos analyzed. These results indicate important roles for both Apaf1 and Bcl2l in inner ear development.

Three time windows for amnestic effect of antibodies to cell adhesion molecule L1 in chicks

THE L1/NgCAM cell adhesion molecule is involved in neurite outgrowth, axonal fasciculation and cell migration in the nervous system. We studied the effects of antibodies against L1 injected intracranially at various times before and after training 2-day-old chicks in a visual categorization task. Memory retention was tested 24h post-training. Anti-L1 antibodies impaired task retention only when administered in three restricted time windows: immediately before training, at about 5.h after training and from 15 to 18h after training.No amnesia was produced by injections before, between or after these sensitive periods (from −1 to +21h relative to training). These results indicate that there are multiple post-training periods during which L1 is involved in the formation of long-term memory.

Mice in Bion-M 1 Space Mission: Training and Selection

After a 16-year hiatus, Russia has resumed its program of biomedical research in space, with the successful 30-day flight of the Bion-M 1 biosatellite (April 19–May 19, 2013). The principal species for biomedical research in this project was the mouse. This paper presents an overview of the scientific goals, the experimental design and the mouse training/selection program. The aim of mice experiments in the Bion-M 1 project was to elucidate cellular and molecular mechanisms, underlying the adaptation of key physiological systems to long-term exposure in microgravity. The studies with mice combined in vivo measurements, both in flight and post-flight (including continuous blood pressure measurement), with extensive in vitro studies carried out shortly after return of the mice and in the end of recovery study. Male C57/BL6 mice group housed in space habitats were flown aboard the Bion-M 1 biosatellite, or remained on ground in the control experiment that replicated environmental and housing conditions in the spacecraft. Vivarium control groups were used to account for housing effects and possible seasonal differences. Mice training included the co-adaptation in housing groups and mice adaptation to paste food diet. The measures taken to co-adapt aggressive male mice in housing groups and the peculiarities of “space” paste food are described. The training program for mice designated for in vivo studies was broader and included behavioral/functional test battery and continuous behavioral measurements in the home-cage. The results of the preliminary tests were used for the selection of homogenous groups. After the flight, mice were in good condition for biomedical studies and displayed signs of pronounced disadaptation to Earths gravity. The outcomes of the training program for the mice welfare are discussed. We conclude that our training program was effective and that male mice can be successfully employed in space biomedical research.

Tailoring the soliton output of a photonic crystal fiber for enhanced two-photon excited luminescence response from fluorescent protein biomarkers and neuron activity reporters

Dual-cladding photonic crystal fibers (PCFs) with two zero-dispersion points are used to enhance the two-photon excited luminescence (TPL) response from fluorescent protein biomarkers and neuron activity reporters in dye-cell experiments and in in vivo work on transgenic mice and tadpoles. The soliton transmission of ultrashort pulses through a PCF suppresses dispersion-induced temporal pulse spreading, maintaining a high level of field intensity needed for efficient TPL excitation. The soliton self-frequency shift, stabilized against laser power fluctuations by a specific PCF dispersion design, is employed to accurately match the wavelength of the soliton PCF output with the two-photon absorption spectrum of dye or fluorescent protein biomarker molecules, enhancing their TPL response and allowing the laser damage of biotissues to be avoided.

Genetic ablation of the mammillary bodies in the Foxb1 mutant mouse leads to selective deficit of spatial working memory

Mammillary bodies and the mammillothalamic tract are parts of a classic neural circuitry that has been implicated in severe memory disturbances accompanying Korsakoffs syndrome. However, the specific role of mammillary bodies in memory functions remains controversial, often being considered as just an extension of the hippocampal memory system. To study this issue we used mutant mice with a targeted mutation in the transcription factor gene Foxb1. These mice suffer perinatal degeneration of the medial and most of the lateral mammillary nuclei, as well as of the mammillothalamic bundle. Foxb1 mutant mice showed no deficits in such hippocampal‐dependent tasks as contextual fear conditioning and social transmission of food preference. They were also not impaired in the spatial reference memory test in the radial arm maze. However, Foxb1 mutants showed deficits in the task for spatial navigation within the Barnes maze. Furthermore, they showed impairments in spatial working memory tasks such as the spontaneous alternation and the working memory test in the radial arm maze. Thus, our behavioural analysis of Foxb1 mutants suggests that the medial mammillary nuclei and mammillothalamic tract play a role in a specific subset of spatial tasks, which require combined use of both spatial and working memory functions. Therefore, the mammillary bodies and the mammillothalamic tract may form an important route through which the working memory circuitry receives spatial information from the hippocampus.

Implantable fiber-optic interface for parallel multisite long-term optical dynamic brain interrogation in freely moving mice

Seeing the big picture of functional responses within large neural networks in a freely functioning brain is crucial for understanding the cellular mechanisms behind the higher nervous activity, including the most complex brain functions, such as cognition and memory. As a breakthrough toward meeting this challenge, implantable fiber-optic interfaces integrating advanced optogenetic technologies and cutting-edge fiber-optic solutions have been demonstrated, enabling a long-term optogenetic manipulation of neural circuits in freely moving mice. Here, we show that a specifically designed implantable fiber-optic interface provides a powerful tool for parallel long-term optical interrogation of distinctly separate, functionally different sites in the brain of freely moving mice. This interface allows the same groups of neurons lying deeply in the brain of a freely behaving mouse to be reproducibly accessed and optically interrogated over many weeks, providing a long-term dynamic detection of genome activity in response to a broad variety of pharmacological and physiological stimuli.