Search

The vertebrate stress response comprises a suite of behavioural and physiological traits that must be functionally integrated to ensure organisms cope adaptively with acute stressors. Natural selection should favour functional integration, leading to a prediction of genetic integration of these traits. Despite the implications of such genetic integration for our understanding of human and animal health, as well as evolutionary responses to natural and anthropogenic stressors, formal quantitative genetic tests of this prediction are lacking. Here, we demonstrate that acute stress response components in Trinidadian guppies are both heritable and integrated on the major axis of genetic covariation. This integration could either facilitate or constrain evolutionary responses to selection, depending upon the alignment of selection with this axis. Such integration also suggests artificial selection on the genetically correlated behavioural responses to stress could offer a viable non-invasive route to the improvement of health and welfare in captive animal populations.

A primary goal of translational neuroscience is to identify the neural mechanisms of age-related cognitive decline and develop protocols to maximally improve cognition. Here, we demonstrate how interventions that apply noninvasive neurostimulation to older adults improve working memory (WM). We found that one session of sham-controlled transcranial direct current stimulation (tDCS) selectively improved WM in older adults with more education, extending earlier work and underscoring the importance of identifying individual predictors of tDCS responsivity. Improvements in WM were associated with two distinct electrophysiological signatures. First, a broad enhancement of theta network synchrony tracked improvements in behavioral accuracy, with tDCS effects moderated by education level. Further analysis revealed that accuracy dynamics reflected an anterior-posterior network distribution regardless of cathode placement. Second, specific enhancements of theta-gamma phase-amplitude coupling (PAC) reflecting tDCS current flow tracked improvements in reaction time (RT). RT dynamics further explained inter-individual variability in WM improvement independent of education. These findings illuminate theta network synchrony and theta-gamma PAC as distinct but complementary mechanisms supporting WM in aging. Both mechanisms are amenable to intervention, the effectiveness of which can be predicted by individual demographic factors.

Auditory gamma-band (>30 Hz) activity is a biomarker of cortical excitation/inhibition (E/I) balance in autism, schizophrenia, and bipolar disorder. We provide a comprehensive account of the effects of transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) on gamma responses. Forty-five healthy young adults listened to 40-Hz auditory click trains while electroencephalography (EEG) data were collected to measure stimulus-related gamma activity immediately before and after 10 min of 1 mA tACS (40 Hz), tDCS, or sham stimulation to left auditory cortex. tACS, but not tDCS, increased gamma power and phase locking to the auditory stimulus. However, both tACS and tDCS strengthened the gamma phase connectome, and effects persisted beyond the stimulus. Finally, tDCS strengthened the coupling of gamma activity to alpha oscillations after termination of the stimulus. No effects were observed in prestimulus gamma power, the gamma amplitude connectome, or any band-limited alpha measure. Whereas both stimulation techniques synchronize gamma responses between regions, tACS also tunes the magnitude and timing of gamma responses to the stimulus. Results reveal dissociable neurophysiological changes following tACS and tDCS and demonstrate that clinical biomarkers can be altered with noninvasive neurostimulation, especially frequency-tuned tACS.NEW & NOTEWORTHY Gamma frequency-tuned transcranial alternating current stimulation (tACS) adjusts the magnitude and timing of auditory gamma responses, as compared with both sham stimulation and transcranial direct current stimulation (tDCS). However, both tACS and tDCS strengthen the gamma phase connectome, which is disrupted in numerous neurological and psychiatric disorders. These findings reveal dissociable neurophysiological changes following two noninvasive neurostimulation techniques commonly applied in clinical and research settings.

Studies in mice using germfree animals as controls for microbial colonization have shown that the gut microbiome mediates diet-induced obesity. Such studies use diets rich in saturated fat, however, Western diets in the United States America are enriched in soybean oil, composed of unsaturated fatty acids, either linoleic or oleic acid. Here, we addressed whether the microbiome is a variable in fat metabolism in mice on a soybean oil diet. We used conventionally-raised, low-germ, and germfree mice fed for 10 weeks diets either high or low in high-linoleic-acid soybean oil as the sole source of fat. Conventional and germfree mice gained relative fat weight and all mice consumed more calories on the high fat vs. low fat soybean oil diet. Plasma fatty acid levels were generally dependent on diet, with microbial colonization status affecting iso-C18:0, C20:3n-6, C14:0, and C15:0 levels. Colonization status, but not diet, impacted levels of liver sphingolipids including ceramides, sphingomyelins, and sphinganine. Our results confirm that absorbed fatty acids are mainly a reflection of the diet and that microbial colonization influences liver sphingolipid pools regardless of diet.

Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

Cell migration is a highly conserved process involving cytoskeletal reorganization and restructuring of the surrounding extracellular matrix. Although there are many studies describing mechanisms underlying cell motility, little has been reported about the contribution of alternative isoform use toward cell migration. Here, we investigated whether alternative isoform use can affect cell migration focusing on reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an established inhibitor of cell migration. We found that a shorter isoform of RECK is more highly expressed in proliferating fibroblasts, in TGF-β–treated fibroblasts, and in tumors compared with differentiated tissue. Knockdown of this short RECK isoform reduces fibroblast migration through Matrigel. Thus, this short isoform of RECK generated by a combination of alternative splicing and alternative polyadenylation plays an opposing role to the canonical RECK isoform, as knockdown of canonical RECK results in faster cell migration through Matrigel. We show that the short RECK protein competes with matrix metalloprotease 9 (MMP9) for binding to the Kazal motifs of canonical RECK, thus liberating MMP9 from an inactivating interaction with canonical RECK. Our studies provide a new paradigm and a detailed mechanism for how alternative isoform use can regulate cell migration by producing two proteins with opposing effects from the same genetic locus.

Recent advances in human cognitive neuroscience show great promise in extending our understanding of the neural basis of memory development. We briefly review the current state of knowledge, highlighting that most work has focused on describing the neural correlates of memory in cross-sectional studies. We then delineate three examples of the application of innovative methods in addressing questions that go beyond description, towards a mechanistic understanding of memory development. First, structural brain imaging and the harmonization of measurements across laboratories may uncover ways in which the maturation of the brain constrains the development of specific aspects of memory. Second, longitudinal designs and sophisticated modeling of the data may identify age-driven changes and the factors that determine individual developmental trajectories. Third, recording memory-related activity directly from the developing brain presents an unprecedented opportunity to examine how distinct brain structures support memory in real time. Finally, the growing prevalence of data sharing offers additional means to tackle questions that demand large-scale datasets, ambitious designs, and access to rare samples. We propose that the use of such innovative methods will move our understanding of memory development from a focus on describing trends to explaining the causal factors that shape behavior. Keywords: Hippocampus, Prefrontal cortex, Structural MRI, Functional MRI, Longitudinal design, ECoG

Intracranial EEG provides spatiotemporally precise evidence that prefrontal cortex maturation partially drives memory development., Prevailing theories link prefrontal cortex (PFC) maturation to the development of declarative memory. However, the precise spatiotemporal correlates of memory formation in the developing brain are not known. We provide rare intracranial evidence that the spatiotemporal propagation of frontal activity supports memory formation in children. Seventeen subjects (6.2 to 19.4 years) studied visual scenes in preparation for a recognition memory test while undergoing direct cortical monitoring. Earlier PFC activity predicted greater accuracy, and subsecond deviations in activity flow between subregions predicted memory formation. Activity flow between inferior and precentral sites was refined during adolescence, partially explaining gains in memory. In contrast, middle frontal activity predicted memory independent of age. These findings show with subsecond temporal precision that the developing PFC links scene perception and memory formation and underscore the role of the PFC in supporting memory development.

The ability to represent and select information in working memory provides the neurobiological infrastructure for human cognition. For 80 years, dominant views of working memory have focused on the key role of prefrontal cortex (PFC) [1–8]. However, more recent work has implicated posterior cortical regions [9–12], suggesting that PFC engagement during working memory is dependent on the degree of executive demand. We provide evidence from neurological patients with discrete PFC damage that challenges the dominant models attributing working memory to PFC-dependent systems. We show that neural oscillations, which provide a mechanism for PFC to communicate with posterior cortical regions [13], independently subserve communications both to and from PFC – uncovering parallel oscillatory mechanisms for working memory. Fourteen PFC patients and 20 healthy, age-matched controls performed a working memory task where they encoded, maintained, and actively processed information about pairs of common shapes. In controls, the electroencephalogram (EEG) exhibited oscillatory activity in the low-theta range over PFC and directional connectivity from PFC to parieto-occipital regions commensurate with executive processing demands. Concurrent alpha-beta oscillations were observed over parieto-occipital regions, with directional connectivity from parieto-occipital regions to PFC, regardless of processing demands. Accuracy, PFC low-theta activity, and PFC ➔ parieto-occipital connectivity were attenuated in patients, revealing a PFC-independent, alpha-beta system. The PFC patients still demonstrated task proficiency, which indicates that the posterior alpha-beta system provides sufficient resources for working memory. Taken together, our findings reveal neurologically dissociable PFC and parieto-occipital systems, and suggest that parallel, bidirectional oscillatory systems form the basis of working memory.

OBJECTIVES: Obesity has been thought to predispose patients to excess morbidity after lung resection because of decreased diaphragm excursion, reduced lung volumes and relative immobility. We assessed the relationship of body mass index (BMI) to acute outcomes after major lung resection. METHODS: Information from our database of lung resections was evaluated for the period 1980–2011. Univariate analysis for adverse events (pulmonary, cardiovascular, other and overall) was used to select variables for inclusion in multivariate logistic regression analyses. Missing values were imputed. BMI was categorized as underweight (

Proteasome inhibition is an approved cancer therapy. Quiescent fibroblasts are much more resistant to proteasome inhibition–induced death than proliferating fibroblasts. Mechanisms that protect quiescent fibroblasts include autophagy/lysosomal pathways, diminished aggresome formation, and detoxification of reactive oxygen species., Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition–mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition–induced cytotoxicity.

How do we rapidly process incoming streams of information in working memory, a cognitive mechanism central to human behavior? Dominant views of working memory focus on the prefrontal cortex (PFC), but human hippocampal recordings provide a neurophysiological signature distinct from the PFC. Are these regions independent, or do they interact in the service of working memory? We addressed this core issue in behavior by recording directly from frontotemporal sites in humans performing a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. Theta band oscillations drove bidirectional interactions between the PFC and medial temporal lobe (MTL; including the hippocampus). MTL theta oscillations directed the PFC preferentially during the processing of spatiotemporal information, while PFC theta oscillations directed the MTL for all types of information being processed in working memory. These findings reveal an MTL theta mechanism for processing space and time and a domain-general PFC theta mechanism, providing evidence that rapid, dynamic MTL–PFC interactions underlie working memory for everyday experiences., Author summary How do we rapidly process incoming streams of information in working memory? Dominant views of working memory focus on the prefrontal cortex (PFC), but other data suggest a role for the medial temporal lobe (MTL). To delineate whether (and how) these brain regions interact during working memory, we recorded directly from PFC and MTL sites in humans performing a task that tests working memory for the types of “what,” “where,” and “when” information encountered every day. MTL oscillations in the theta band (3–7 Hz) directed PFC activity during the processing of spatiotemporal information, while PFC theta oscillations directed MTL activity for all types of information. This functional dissociation provides the first demonstration of bidirectional communication between the PFC and MTL during working memory. Our findings reveal that rapid, dynamic interactions between these two regions underlie working memory for everyday experiences, challenging dominant views on the central role of the PFC.

This study investigated whether the age-related positivity effect strengthens specific event details in autobiographical memory. Participants retrieved past events or imagined future events in response to neutral or emotional cue words. Older adults rated each kind of event more positively than younger adults, demonstrating an age-related positivity effect. We next administered a source memory test. Participants were given the same cue words and tried to retrieve the previously generated event and its source (past or future). Accuracy on this source test should depend on the recollection of specific details about the earlier generated events, providing a more objective measure of those details than subjective ratings. We found that source accuracy was greater for positive than negative future events in both age groups, suggesting that positive future events were more detailed. In contrast, valence did not affect source accuracy for past events in either age group, suggesting that positive and negative past events were equally detailed. Although ageing can bias people to focus on positive aspects of experience, this bias does not appear to strengthen the availability of details for positive relative to negative past events.

Organisms must make important decisions on how to allocate resources to reproduction. We investigated allocation decisions in the social wasp Vespula maculifrons to understand how social insects make reproductive choices. We first determined how annual colonies apportioned resources to growth and reproduction by analysing developing brood. In contrast to expectations, colonies invested in both growth (workers) and reproduction (males) simultaneously. In addition, colonies showed evidence of producing males in pulses and reversing their reproductive choices by decreasing investment in males late in the season. This reversal is consistent with theory suggesting that colonies decrease production in males if fitness of late emerging males is low. To further investigate reproductive decisions within colonies, we determined if the male mates of multiply-mated queens varied in their reproductive success over time. Sperm use by queens did vary over time suggesting that male success may depend on sperm clumping within the female reproductive tract. Finally, we tested if colony sex ratio conformed to expectations under kin selection theory that nestmate relatedness would positively correlate with investment in new queens if workers controlled sex allocation. Surprisingly, the proportion of queens produced by colonies was negatively correlated with nestmate relatedness, suggesting that allocation may be shaped by advantages arising from increased genetic diversity resulting from multiple mating by queens. Overall, our study suggests that the reproductive decisions of colonies are flexible and may depend both on environmental cues arising from energetic needs of the colony and genetic cues arising from mating behaviours of queens.