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.

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

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.

22The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting 23 task in an opposite manner. A recently developed theory suggests that this pattern of 24 behavior may be representative of predicted effects of imprinted genes on tolerance to risk. 25Here we examine whether mice lacking paternal expression of Grb10 show abnormal 26 behavior across a number of measures indicative of risk-taking. Although Grb10 +/p mice 27 show no difference from wild type littermates in their willingness to explore a novel 28 environment, their behavior on an explicit test of risk-taking, namely the Predator Odour 29Risk-Taking task, is indicative of an increased willingness to take risks. Follow-up tests 30 suggest that this risk-taking is not simply due to a general decrease in fear, or a general 31 increase in motivation for a food reward, but reflects a change in the trade-off between cost 32 and reward. These data, coupled with previous work on the impulsive behaviour of Grb10 +/p 33 mice in the delayed reinforcement task, and taken together with our work on mice lacking 34 maternal Nesp, suggest that maternally and paternally expressed imprinted genes oppositely 35 influence risk-taking behaviour as predicted. 36

No abstract

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 currently 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 wildtype 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 on the stability of social behaviors, rather than dominance per se.

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.

No abstract