Combined space stressors induce independent behavioral deficits predicted by early peripheral blood monocytes.

Interplanetary space travel poses many hazards to the human body. To protect astronaut health and performance on critical missions, there is first a need to understand the effects of deep space hazards, including ionizing radiation, confinement, and altered gravity. Previous studies of rodents exposed to a single such stressor document significant deficits, but our study is the first to investigate possible cumulative and synergistic impacts of simultaneous ionizing radiation, confinement, and altered gravity on behavior and cognition. Our cohort was divided between 6-month-old female and male mice in group, social isolation, or hindlimb unloading housing, exposed to 0 or 50 cGy of 5 ion simplified simulated galactic cosmic radiation (GCRsim). We report interactions and independent effects of GCRsim exposure and housing conditions on behavioral and cognitive performance. Exposure to GCRsim drove changes in immune cell populations in peripheral blood collected early after irradiation, while housing conditions drove changes in blood collected at a later point. Female mice were largely resilient to deficits observed in male mice. Finally, we used principal component analysis to represent total deficits as principal component scores, which were predicted by general linear models using GCR exposure, housing condition, and early blood biomarkers.

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR-even weeks after injury-can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus.

Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.

Microglia: Ally and Enemy in Deep Space.

In 2024 the first female astronaut will land on the moon, advancing our preparations for human missions to Mars. While on Earth we are protected from space radiation by our planet's magnetic field, on such deep space voyages astronauts will be exposed to high energy particles from solar flares and galactic cosmic rays (GCR). This exposure carries risks to the central nervous system (CNS) that could jeopardize the mission and astronaut health. Earth-bound studies have employed a variety of single-beam and sequential radiation exposures to simulate the effects of GCR exposure in rodents. Multiple studies have shown that GCR simulation induces a maladaptive activation of microglia - the brain-resident immune cells. GCR simulation also induced synaptic changes resulting in lasting cognitive and behavioral defects. Female and male mice show different susceptibilities to GCR exposure, and evidence suggests this sexually dimorphic response is linked to microglia. Manipulating microglia can prevent the development of cognitive deficits in male mice exposed to components of GCR. This discovery may provide clues towards how to protect astronauts' cognitive and behavioral health both during deep space missions and upon return to Earth.

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium.

Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments in vitro are criticized for being poor representatives of in vivo phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment in vitro, the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.

Mice lacking paternal expression of imprinted Grb10 are risk-takers.

The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting task in an opposite manner. A recently developed theory suggests that this pattern of behavior may be representative of predicted effects of imprinted genes on tolerance to risk. Here we examine whether mice lacking paternal expression of Grb10 show abnormal behavior across a number of measures indicative of risk-taking. Although Grb10+/p mice show no difference from wild type (WT) littermates in their willingness to explore a novel environment, their behavior on an explicit test of risk-taking, namely the Predator Odor Risk-Taking task, is indicative of an increased willingness to take risks. Follow-up tests suggest that this risk-taking is not simply because of a general decrease in fear, or a general increase in motivation for a food reward, but reflects a change in the trade-off between cost and reward. These data, coupled with previous work on the impulsive behavior of Grb10+/p mice in the delayed reinforcement task, and taken together with our work on mice lacking maternal Nesp, suggest that maternally and paternally expressed imprinted genes oppositely influence risk-taking behavior as predicted.

Detailed analysis of paternal knockout Grb10 mice suggests effects on stability of social behavior, rather than social dominance.

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is generally recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10 +/p mice. Moreover, the original study examined tube-test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10 +/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences and tested cohorts aged 2, 6 and 10 months to examine any developments related to age. We found group-housed Grb10 +/p mice do not show evidence of enhanced social dominance, but cages containing Grb10 +/p and wild-type mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10 +/p mice should focus on the stability of social behaviors, rather than dominance per se.