Parasites alter food-web topology of a subarctic lake food web and its pelagic and benthic compartments.

We compared three sets of highly resolved food webs with and without parasites for a subarctic lake system corresponding to its pelagic and benthic compartments and the whole-lake food web. Key topological food-web metrics were calculated for each set of compartments to explore the role parasites play in food-web topology in these highly contrasting webs. After controlling for effects from differences in web size, we observed similar responses to the addition of parasites in both the pelagic and benthic compartments demonstrated by increases in trophic levels, linkage density, connectance, generality, and vulnerability despite the contrasting composition of free-living and parasitic species between the two compartments. Similar effects on food-web topology can be expected with the inclusion of parasites, regardless of the physical characteristics and taxonomic community compositions of contrasting environments. Additionally, similar increases in key topological metrics were found in the whole-lake food web that combines the pelagic and benthic webs, effects that are comparable to parasite food-web analyses from other systems. These changes in topological metrics are a result of the unique properties of parasites as infectious agents and the links they participate in. Trematodes were key contributors to these results, as these parasites have distinct characteristics in aquatic systems that introduce new link types and increase the food web's generality and vulnerability disproportionate to other parasites. Our analysis highlights the importance of incorporating parasites, especially trophically transmitted parasites, into food webs as they significantly alter key topological metrics and are thus essential for understanding an ecosystem's structure and functioning.

Deriving early single-rosette brain organoids from human pluripotent stem cells.

Brain organoid methods are complicated by multiple rosette structures and morphological variability. We have developed a human brain organoid technique that generates self-organizing, single-rosette cortical organoids (SOSR-COs) with reproducible size and structure at early timepoints. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D developmental transition from neural plate to neural tube. Most monolayer fragments form spheres with a single central lumen. Over time, the SOSR-COs develop appropriate progenitor and cortical laminar cell types as shown by immunocytochemistry and single-cell RNA sequencing. At early time points, this method demonstrates robust structural phenotypes after chemical teratogen exposure or when modeling a genetic neurodevelopmental disorder, and should prove useful for studies of human brain development and disease modeling.

High emotional reactivity is associated with activation of a molecularly distinct hippocampal-amygdala circuit modulated by the glucocorticoid receptor.

Emotions are characterized not only by their valence but also by whether they are stable or labile. Yet, we do not understand the molecular or circuit mechanisms that control the dynamic nature of emotional responses. We have shown that glucocorticoid receptor overexpression in the forebrain (GRov) leads to a highly reactive mouse with increased anxiety behavior coupled with greater swings in emotional responses. This phenotype is established early in development and persists into adulthood. However, the neural circuitry mediating this lifelong emotional lability remains unknown. In the present study, optogenetic stimulation in ventral dentate gyrus (vDG) of GRov mice led to a greater range and a prolonged duration of anxiety behavior. cFos expression analysis showed that the amplified behavioral response to vDG activation in GRov mice is coupled to increased neuronal activity in specific brain regions. Relative to wild type mice, GRov mice displayed glutamatergic/GABAergic activation imbalance in ventral CA1 (vCA1) and selectively increased glutamatergic activation in the basal posterior amygdaloid complex. Moreover, forebrain GR overexpression led to increased activation of molecularly distinct subpopulations of neurons within the hippocampus and the posterior basolateral amygdala (pBLA) as evident from the increased cFos co-labeling in the calbindin1+ glutamatergic neurons in vCA1 and in the DARPP-32/Ppp1r1b+ glutamatergic neurons in pBLA. We propose that a molecularly distinct hippocampal-amygdala circuit is shaped by stress early in life and tunes the dynamics of emotional responses.

Age-related deficits in neuronal physiology and cognitive function are recapitulated in young mice overexpressing the L-type calcium channel, CaV 1.3.

The calcium dysregulation hypothesis of brain aging posits that an age-related increase in neuronal calcium concentration is responsible for alterations in a variety of cellular processes that ultimately result in learning and memory deficits in aged individuals. We previously generated a novel transgenic mouse line, in which expression of the L-type voltage-gated calcium, CaV 1.3, is increased by ~50% over wild-type littermates. Here, we show that, in young mice, this increase is sufficient to drive changes in neuronal physiology and cognitive function similar to those observed in aged animals. Specifically, there is an increase in the magnitude of the postburst afterhyperpolarization, a deficit in spatial learning and memory (assessed by the Morris water maze), a deficit in recognition memory (assessed in novel object recognition), and an overgeneralization of fear to novel contexts (assessed by contextual fear conditioning). While overexpression of CaV 1.3 recapitulated these key aspects of brain aging, it did not produce alterations in action potential firing rates, basal synaptic communication, or spine number/density. Taken together, these results suggest that increased expression of CaV 1.3 in the aged brain is a crucial factor that acts in concert with age-related changes in other processes to produce the full complement of structural, functional, and behavioral outcomes that are characteristic of aged animals.

Patched and Costal-2 mutations lead to differences in tissue overgrowth autonomy.

Genetic screens are used in Drosophila melanogaster to identify genes key in the regulation of organismal development and growth. These screens have defined signalling pathways necessary for tissue and organismal development, which are evolutionarily conserved across species, including Drosophila. Here, we have used an FLP/FRT mosaic system to screen for conditional regulators of cell growth and cell division in the Drosophila eye. The conditional nature of this screen utilizes a block in the apoptotic pathway to prohibit the mosaic mutant cells from dying via apoptosis. From this screen, we identified two different mutants that mapped to the Hedgehog signalling pathway. Previously, we described a novel Ptc mutation and here we add to the understanding of disrupting the Hh pathway with a novel allele of Cos2. Both of these Hh components are negative regulators of the pathway, yet they depict mutant differences in the type of overgrowth created. Ptc mutations lead to overgrowth consisting of almost entirely wild-type tissue (non-autonomous overgrowth), while the Cos2 mutation results in tissue that is overgrown in both the mutant and wild-type clones (both autonomous and non-autonomous). These differences in tissue overgrowth are consistent in the Drosophila eye and wing. The observed difference is correlated with different deregulation patterns of pMad, the downstream effector of DPP signalling. This finding provides insight into pathway-specific differences that help to better understand intricacies of developmental processes and human diseases that result from deregulated Hedgehog signalling, such as basal cell carcinoma.

Super-Spreaders or Victims of Circumstance? Childhood in Canadian Media Reporting of the COVID-19 Pandemic: A Critical Content Analysis.

This qualitative research study, a critical content analysis, explores Canadian media reporting of childhood in Canada during the COVID-19 global pandemic. Popular media plays an important role in representing and perpetuating the dominant social discourse in highly literate societies. In Canadian media, the effects of the pandemic on children and adolescents' health and wellbeing are overshadowed by discussions of the potential risk they pose to adults. The results of this empirical research highlight how young people in Canada have been uniquely impacted by the COVID-19 global pandemic. Two dominant narratives emerged from the data: children were presented "as a risk" to vulnerable persons and older adults and "at risk" of adverse health outcomes from contracting COVID-19 and from pandemic lockdown restrictions. This reflects how childhood was constructed in Canadian society during the pandemic, particularly how children's experiences are described in relation to adults. Throughout the pandemic, media reports emphasized the role of young people's compliance with public health measures to prevent the spread of COVID-19 and save the lives of older persons.

Tissue Plasminogen Activator in Central Nervous System Physiology and Pathology: From Synaptic Plasticity to Alzheimer's Disease.

Tissue plasminogen activator's (tPA) fibrinolytic function in the vasculature is well-established. This specific role for tPA in the vasculature, however, contrasts with its pleiotropic activities in the central nervous system. Numerous physiological and pathological functions have been attributed to tPA in the central nervous system, including neurite outgrowth and regeneration; synaptic and spine plasticity; neurovascular coupling; neurodegeneration; microglial activation; and blood-brain barrier permeability. In addition, multiple substrates, both plasminogen-dependent and -independent, have been proposed to be responsible for tPA's action(s) in the central nervous system. This review aims to dissect a subset of these different functions and the different molecular mechanisms attributed to tPA in the context of learning and memory. We start from the original research that identified tPA as an immediate-early gene with a putative role in synaptic plasticity to what is currently known about tPA's role in a learning and memory disorder, Alzheimer's disease. We specifically focus on studies demonstrating tPA's involvement in the clearance of amyloid-ß and neurovascular coupling. In addition, given that tPA has been shown to regulate blood-brain barrier permeability, which is perturbed in Alzheimer's disease, this review also discusses tPA-mediated vascular dysfunction and possible alternative mechanisms of action for tPA in Alzheimer's disease pathology.

Shotgun slug wads as a marker of range of fire: A case report and novel firearm testing data.

Assessment of wound characteristics and the identification of various constituents of firearm discharge at autopsy play a key role in the determination of range of fire. In relation to wounds caused by shotguns, identification of the wad within the wound track, or of injury caused by the wad, is typically thought to suggest a fairly close range of fire. We present a case of a fatality due to a shotgun slug wound where the presence of the wad within the decedent's body was proposed by defense at criminal trial to favor accidental close range discharge during a struggle for the weapon-as opposed to the prosecution's contention of intentional firing of the weapon from a greater range and through an intermediate target. We undertook test firing of a shotgun of similar design to that which was fired during the interaction (a 12-gauge pump-action shotgun) using shotshells consistent with the slug that was recovered from the body (Winchester Super X brand), which demonstrated that the non-attached fiber wad present in this shotshell design can accompany the slug over distances of at least up to 22 feet (6.7 m) and even after transit through intermediate targets such as a vehicle headrest. These novel data provide assistance with estimation of range of fire in instances of injuries caused by shotgun slugs.

Novel Asaia bogorensis Signal Sequences for Plasmodium Inhibition in Anopheles stephensi.

Mosquitoes vector many pathogens that cause human disease, such as malaria that is caused by parasites in the genus Plasmodium. Current strategies to control vector-transmitted diseases are hindered by mosquito and pathogen resistance, so research has turned to altering the microbiota of the vectors. In this strategy, called paratransgenesis, symbiotic bacteria are genetically modified to affect the mosquito's phenotype by engineering them to deliver antiplasmodial effector molecules into the midgut to kill parasites. One paratransgenesis candidate is Asaia bogorensis, a Gram-negative, rod-shaped bacterium colonizing the midgut, ovaries, and salivary glands of Anopheles sp. mosquitoes. However, common secretion signals from E. coli and closely related species do not function in Asaia. Here, we report evaluation of 20 native Asaia N-terminal signal sequences predicted from bioinformatics for their ability to mediate increased levels of antiplasmodial effector molecules directed to the periplasm and ultimately outside the cell. We tested the hypothesis that by increasing the amount of antiplasmodials released from the cell we would also increase parasite killing power. We scanned the Asaia bogorensis SF2.1 genome to identify signal sequences from extra-cytoplasmic proteins and fused these to the reporter protein alkaline phosphatase. Six signals resulted in significant levels of protein released from the Asaia bacterium. Three signals were successfully used to drive the release of the antimicrobial peptide, scorpine. Further testing in mosquitoes demonstrated that these three Asaia strains were able to suppress the number of oocysts formed after a blood meal containing P. berghei to a significantly greater degree than wild-type Asaia, although prevalence was not decreased beyond levels obtained with a previously isolated siderophore receptor signal sequence. We interpret these results to indicate that there is a maximum level of suppression that can be achieved when the effectors are constitutively driven due to stress on the symbionts. This suggests that simply increasing the amount of antiplasmodial effector molecules in the midgut is insufficient to create superior paratransgenic bacterial strains and that symbiont fitness must be considered as well.

Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity.

The aggregation of amyloidogenic polypeptides is strongly linked to several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Conformational antibodies that selectively recognize protein aggregates are leading therapeutic agents for selectively neutralizing toxic aggregates, diagnostic and imaging agents for detecting disease, and biomedical reagents for elucidating disease mechanisms. Despite their importance, it is challenging to generate high-quality conformational antibodies in a systematic and site-specific manner due to the properties of protein aggregates (hydrophobic, multivalent, and heterogeneous) and limitations of immunization (uncontrolled antigen presentation and immunodominant epitopes). Toward addressing these challenges, we have developed a systematic directed evolution procedure for affinity maturing antibodies against Alzheimer's Aß fibrils and selecting variants with strict conformational and sequence specificity. We first designed a library based on a lead conformational antibody by sampling combinations of amino acids in the antigen-binding site predicted to mediate high antibody specificity. Next, we displayed this library on the surface of yeast, sorted it against Aß42 aggregates, and identified promising clones using deep sequencing. The resulting antibodies displayed similar or higher affinities than clinical-stage Aß antibodies (aducanumab and crenezumab). Moreover, the affinity-matured antibodies retained high conformational specificity for Aß aggregates, as observed for aducanumab and unlike crenezumab. Notably, the affinity-maturated antibodies displayed extremely low levels of nonspecific interactions, as observed for crenezumab and unlike aducanumab. We expect that our systematic methods for generating antibodies with unique combinations of desirable properties will improve the generation of high-quality conformational antibodies specific for diverse types of aggregated conformers.

A Helminth Survey of Northern Bobwhite Quail (Colinus virginianus) and Passerines in the Rolling Plains Ecoregion of Texas.

The Northern bobwhite quail (Colinus virginianus) is a popular game bird that has been experiencing a well-documented decline throughout Texas since the 1960s. While much of this decline has been attributed to habitat loss and fragmentation, recent studies have identified other factors that may also contribute to decreasing quail populations. Parasites, in particular, have become increasingly recognized as possible stressors of quail, and some species, particularly the eyeworm (Oxyspirura petrowi) and cecal worm (Aulonocephalus pennula) are highly prevalent in Texas quails. Eyeworm infection has also been documented in some passerines, suggesting helminth infection may be shared between bird species. However, the lack of comprehensive helminth surveys has rendered the extent of shared infection between quail and passerines in the ecoregion unclear. Thus, helminth surveys were conducted on bobwhite, scaled quail (Callipepla squamata), Northern mockingbirds (Mimus polyglottos), curve-billed thrashers (Toxistoma curvirostre), and Northern cardinals (Cardinalis cardinalis) to contribute data to existing parasitological gaps for birds in the Rolling Plains ecoregion of Texas. Birds were trapped across 3 counties in the Texas Rolling Plains from March to October 2019. Necropsies were conducted on 54 individuals (36 quail and 18 passerines), and extracted helminths were microscopically identified. Nematode, cestode, and acanthocephalan helminths representing at least 10 helminth species were found. Specifically, A. pennula and O. petrowi had the highest prevalence, and O. petrowi was documented in all of the study species. This research adds to the body of knowledge regarding parasitic infections in quail and passerines of the Rolling Plains ecoregion and highlights the potential consequences of shared infection of eyeworms among these bird species.

Individualized fluid management in extremely preterm neonates to ensure adequate diuresis without increasing complications.

OBJECTIVE: Decrease the incidence of inadequate diuresis (ID, loss of <6% of birth weight) in extremely preterm neonates (EPT, <28 weeks of gestation at birth) during the first week of life by 50% in 1 year. STUDY DESIGN: Quality improvement project in a level IV neonatal intensive care unit. A fluid management protocol was implemented, including the use of a fluid guide sheet and closer monitoring of hydration parameters. Seventy-nine baseline EPT neonates were compared to 83 post intervention. The incidence of ID was tracked monthly, along with prespecified morbidities and complications. Statistical data analyses also compared the pre- and post-intervention periods. RESULTS: Fluid volumes in the first week were decreased (p < 0.001). ID decreased from 43 to 29% (p = 0.061). Tracked morbidities and complications were not statistically different. CONCLUSION: Intentional and individualized adjustment of fluids led to decreased ID without increased hypernatremia and dehydration, or a change in tracked morbidities.

Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5×FAD Mice.

BACKGROUND: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-ß production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. OBJECTIVE: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. METHODS: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. RESULTS: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aß load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. CONCLUSION: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD.

Avian and Emerging Human Oxyspirura Species Compared by Morphology, Pathogenicity, Intermediate Host, and Sequence Homology.

Based on sequence homology and phylogenetic tree results, the first report of eyeworm Oxyspirura species larvae has been confirmed in a human patient from Vietnam. However, important information related to Oxyspirura larvae was not presented in the case study. This comment provides a more detailed comparison of the Oxyspirura larvae found in the human case study to the avian eyeworm Oxyspirura petrowi.

Familiarity with teammate's attitudes improves team performance in virtual reality.

Virtual reality (VR) is a potentially challenging social environment for effective communication and collaboration. Thus, we conducted a VR study to determine whether increased familiarity with a teammate would improve performance on a joint decision making task. Specifically, because attitude familiarity, or knowledge of another person's attitudes, has been correlated with better relationship functioning in the past, we anticipated that team performance would improve when teammates were first asked to discuss their task-relevant attitudes with one another. We also hypothesized that increased familiarity would be particularly useful in immersive VR, where typical social and other nonverbal cues were lacking. Twenty pairs recruited from a workplace environment were randomly assigned to either the Familiar or Control condition before completing a joint decision making task both in VR and on desktop monitors. The manipulation of attitude familiarity was successful: pairs in the Familiar condition were significantly more aware of their partners' unique task-relevant attitudes. Results found that in VR, Familiar pairs were more accurate at determining patterns to events. Additionally, for teams less experienced in VR, Familiar pairs were also more accurate at predicting future events. However, there was no meaningful statistical difference in pairs' ability to identify information. Familiar teams also took more time to answer questions, and we found no difference in self-reported communication quality. Overall, this was the first successful manipulation of attitude familiarity and results indicate that such an intervention may prove useful in a collaborative work environment, as Familiar teams demonstrated greater accuracy, especially in VR.

The effectiveness of parental distraction during children's acute pain: The moderating effect of socioeconomic status.

BACKGROUND: Parental responses to children's pain shape how children interpret and cope with pain symptoms through parental modelling and operant conditioning. Evidence suggests that parental distraction is effective in reducing children's acute pain responses, but findings are inconsistent across pain tolerance, intensity and unpleasantness, and are limited to samples of primarily middle and upper-middle class families. Although socioeconomically disadvantaged families may have fewer psychological resources to cope with pain, no studies have examined whether the utility of parent distraction varies by family socioeconomic status (SES). The current study tested the hypothesis that relations between parental distraction and acute pain responses in children vary by family SES, with children from higher versus lower SES families experiencing more substantial benefits. METHODS: Children's pain symptoms and parents' use of verbal distraction during a cold pressor task were examined in a community sample of 530 twin children aged 7-12 years old and their primary caregivers. RESULTS: Parental distraction was positively associated with children's pain tolerance and unrelated to intensity and unpleasantness, but these associations are qualified by significant moderation. In families with higher SES, parental distraction was an effective technique in children's pain management, associated with more pain tolerance and less pain intensity and unpleasantness. However, for families with lower SES, these same benefits were not present. CONCLUSIONS: Findings suggest that the effectiveness of parental distraction for children's acute pain may depend on family SES. SIGNIFICANCE: Study findings suggest that the effects of parental distraction on children's responses to an acute pain task vary by family SES. Although parental distraction may be effective for higher SES children, further research is needed to identify whether and why distraction may not be beneficial for lower SES families.

Modeling UBQLN2-mediated neurodegenerative disease in mice: Shared and divergent properties of wild type and mutant UBQLN2 in phase separation, subcellular localization, altered proteostasis pathways, and selective cytotoxicity.

The ubiquitin-binding proteasomal shuttle protein UBQLN2 is implicated in common neurodegenerative disorders due to its accumulation in disease-specific aggregates and, when mutated, directly causes familial frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). Like other proteins linked to FTD/ALS, UBQLN2 undergoes phase separation to form condensates. The relationship of UBQLN2 phase separation and accumulation to neurodegeneration, however, remains uncertain. Employing biochemical, neuropathological and behavioral assays, we studied the impact of overexpressing WT or mutant UBQLN2 in the CNS of transgenic mice. Expression of UBQLN2 harboring a pathogenic mutation (P506T) elicited profound and widespread intraneuronal inclusion formation and aggregation without prominent neurodegenerative or behavioral changes. Both WT and mutant UBQLN2 formed ubiquitin- and P62-positive inclusions in neurons, supporting the view that UBQLN2 is intrinsically prone to phase separate, with the size, shape and frequency of inclusions depending on expression level and the presence or absence of a pathogenic mutation. Overexpression of WT or mutant UBQLN2 resulted in a dose-dependent decrease in levels of a key interacting chaperone, HSP70, as well as dose-dependent profound degeneration of the retina. We conclude that, at least in mice, robust aggregation of a pathogenic form of UBQLN2 is insufficient to cause neuronal loss recapitulating that of human FTD/ALS. Our results nevertheless support the view that altering the normal cellular balance of UBQLN2, whether wild type or mutant protein, has deleterious effects on cells of the CNS and retina that likely reflect perturbations in ubiquitin-dependent protein homeostasis.

Prevalence of monarch (Danaus plexippus) and queen (Danaus gilippus) butterflies in West Texas during the fall of 2018.

BACKGROUND: The monarch butterfly (Danaus plexippus) is a conspicuous insect that has experienced a drastic population decline over the past two decades. While there are several factors contributing to dwindling monarch populations, habitat loss is considered the most significant threat to monarchs. In the United States, loss of milkweed, particularly in the Midwest, has greatly reduced the available breeding habitat of monarchs. This has led to extensive efforts to conserve and restore milkweed resources throughout the Midwest. Recently, these research and conservation efforts have been expanded to include other important areas along the monarch's migratory path. RESULTS: During the fall of 2018, we conducted surveys of monarch eggs and larvae through West Texas. We documented monarch and queen butterfly (Danaus gilippus) reproduction throughout the region and used the proportion of monarch and queen larva to estimate the number of monarch eggs. Peak egg densities for monarchs were as high as 0.78 per milkweed ramet after correction for the presence of queens. Despite our observations encompassing only a limited sample across one season, the peak monarch egg densities we observed exceeded published reports from when monarch populations were higher. CONCLUSIONS: To our knowledge, this is the first study to correct for the presence of queens when calculating the density of monarch eggs. This research also provides insight into monarch utilization of less well-known regions, such as West Texas, and highlights the need to expand the scope of monarch monitoring and conservation initiatives. While the importance of monarch research and conservation in the Midwest is unquestionable, more comprehensive efforts may identify new priorities in monarch conservation and lead to a more robust and effective overall strategy, particularly given the dynamic and rapidly changing global environment.

Turning strains into strengths for understanding psychiatric disorders.

There is a paucity in the development of new mechanistic insights and therapeutic approaches for treating psychiatric disease. One of the major challenges is reflected in the growing consensus that risk for these diseases is not determined by a single gene, but rather is polygenic, arising from the action and interaction of multiple genes. Canonically, experimental models in mice have been designed to ascertain the relative contribution of a single gene to a disease by systematic manipulation (e.g., mutation or deletion) of a known candidate gene. Because these studies have been largely carried out using inbred isogenic mouse strains, in which there is no (or very little) genetic diversity among subjects, it is difficult to identify unique allelic variants, gene modifiers, and epigenetic factors that strongly affect the nature and severity of these diseases. Here, we review various methods that take advantage of existing genetic diversity or that increase genetic variance in mouse models to (1) strengthen conclusions of single-gene function; (2) model diversity among human populations; and (3) dissect complex phenotypes that arise from the actions of multiple genes.

The role of L-type calcium channels in neuronal excitability and aging.

Over the last two decades there has been significant progress towards understanding the neural substrates that underlie age-related cognitive decline. Although many of the exact molecular and cellular mechanisms have yet to be fully understood, there is consensus that alterations in neuronal calcium homeostasis contribute to age-related deficits in learning and memory. Furthermore, it is thought that the age-related changes in calcium homeostasis are driven, at least in part, by changes in calcium channel expression. In this review, we focus on the role of a specific class of calcium channels: L-type voltage-gated calcium channels (LVGCCs). We provide the reader with a general introduction to voltage-gated calcium channels, followed by a more detailed description of LVGCCs and how they serve to regulate neuronal excitability via the post burst afterhyperpolarization (AHP). We conclude by reviewing studies that link the slow component of the AHP to learning and memory, and discuss how age-related increases in LVGCC expression may underlie cognitive decline by mediating a decrease in neuronal excitability.