Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy.

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.SIGNIFICANCE STATEMENT People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathologic bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE, and supports a long-standing hypothesis of episodic memory theories.

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition.

Patients with epilepsy report that sleep deprivation is a common trigger for breakthrough seizures. The basic mechanism of this phenomenon is unknown. In the Kv1.1-/- mouse model of epilepsy, daily sleep deprivation indeed exacerbated seizures though these effects were lost after the third day. Sleep deprivation also accelerated mortality in ~ 52% of Kv1.1-/- mice, not observed in controls. Voltage-clamp experiments on the day after recovery from sleep deprivation showed reductions in GABAergic tonic inhibition in dentate granule cells in epileptic Kv1.1-/- mice. Our results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition. ANN NEUROL 2021;90:840-844.

Sleep-wake characteristics in a mouse model of severe traumatic brain injury: Relation to posttraumatic epilepsy.

Study objectives: Traumatic brain injury (TBI) results in sequelae that include posttraumatic epilepsy (PTE) and sleep-wake disturbances. Here, we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods: Following controlled cortical impact (CCI) or sham injury (craniotomy only), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2, or 3) 1-week-long video-EEG recordings were performed after the injury to examine epileptiform activity. High-amplitude interictal events were extracted from EEG using an automated method. After scoring sleep-wake patterns, sleep spindles and EEG delta power were derived from nonrapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1-week-long EEG recordings at week 1 and month 1 after surgery. Results: Posttraumatic seizures were seen in the CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep-wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared with NC though the CCI group with posttraumatic seizures had lower power at a chronic time point compared with those without. Follow-up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Significance: In our TBI model, tracking changes in NREM delta power distinguishes between CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

An automated, machine learning-based detection algorithm for spike-wave discharges (SWDs) in a mouse model of absence epilepsy.

OBJECTIVE: Manual detection of spike-wave discharges (SWDs) from electroencephalography (EEG) records is time intensive, costly, and subject to inconsistencies/biases. In addition, manual scoring often omits information on SWD confidence/intensity, which may be important for the investigation of mechanistic-based research questions. Our objective is to develop an automated method for the detection of SWDs in a mouse model of absence epilepsy that is focused on the characteristics of human scoring of preselected events to establish a confidence-based, continuous-valued scoring. METHODS: We develop a support vector machine (SVM)-based algorithm for the automated detection of SWDs in the γ2R43Q mouse model of absence epilepsy. The algorithm first identifies putative SWD events using frequency- and amplitude-based peak detection. Four humans scored a set of 2500 putative events identified by the algorithm. Then, using predictors calculated from the wavelet transform of each event and the labels from human scoring, we trained an SVM to classify (SWD/nonSWD) and assign confidence scores to each event identified from 60, 24-hour EEG records. We provide a detailed assessment of intra- and interrater scoring that demonstrates advantages of automated scoring. RESULTS: The algorithm scored SWDs along a continuum that is highly correlated with human confidence and that allows us to more effectively characterize ambiguous events. We demonstrate that events along our scoring continuum are temporally and proportionately correlated with abrupt changes in spectral power bands relevant to normal behavioral states including sleep. SIGNIFICANCE: Although there are automated and semi-automated methods for the detection of SWDs in humans and rats, we contribute to the need for continued development of SWD detection in mice. Our results demonstrate the value of viewing detection of SWDs as a continuous classification problem to better understand "ground truth" in SWD detection (ie, the most reliable features agreed upon by humans that also correlate with objective physiologic measures).

A predictive epilepsy index based on probabilistic classification of interictal spike waveforms.

Quantification of interictal spikes in EEG may provide insight on epilepsy disease burden, but manual quantification of spikes is time-consuming and subject to bias. We present a probability-based, automated method for the classification and quantification of interictal events, using EEG data from kainate- and saline-injected mice (C57BL/6J background) several weeks post-treatment. We first detected high-amplitude events, then projected event waveforms into Principal Components space and identified clusters of spike morphologies using a Gaussian Mixture Model. We calculated the odds-ratio of events from kainate- versus saline-treated mice within each cluster, converted these values to probability scores, P(kainate), and calculated an Hourly Epilepsy Index for each animal by summing the probabilities for events where the cluster P(kainate) > 0.5 and dividing the resultant sum by the record duration. This Index is predictive of whether an animal received an epileptogenic treatment (i.e., kainate), even if a seizure was never observed. We applied this method to an out-of-sample dataset to assess epileptiform spike morphologies in five kainate mice monitored for ~1 month. The magnitude of the Index increased over time in a subset of animals and revealed changes in the prevalence of epileptiform (P(kainate) > 0.5) spike morphologies. Importantly, in both data sets, animals that had electrographic seizures also had a high Index. This analysis is fast, unbiased, and provides information regarding the salience of spike morphologies for disease progression. Future refinement will allow a better understanding of the definition of interictal spikes in quantitative and unambiguous terms.

Mountain Pine Beetle Dynamics and Reproductive Success in Post-Fire Lodgepole and Ponderosa Pine Forests in Northeastern Utah.

Fire injury can increase tree susceptibility to some bark beetles (Curculionidae, Scolytinae), but whether wildfires can trigger outbreaks of species such as mountain pine beetle (Dendroctonus ponderosae Hopkins) is not well understood. We monitored 1173 lodgepole (Pinus contorta var. latifolia Doug.) and 599 ponderosa (Pinus ponderosa Doug. ex Law) pines for three years post-wildfire in the Uinta Mountains of northeastern Utah in an area with locally endemic mountain pine beetle. We examined how the degree and type of fire injury influenced beetle attacks, brood production, and subsequent tree mortality, and related these to beetle population changes over time. Mountain pine beetle population levels were high the first two post-fire years in lodgepole pine, and then declined. In ponderosa pine, populations declined each year after initial post-fire sampling. Compared to trees with strip or failed attacks, mass attacks occurred on trees with greater fire injury, in both species. Overall, a higher degree of damage to crowns and boles was associated with higher attack rates in ponderosa pines, but additional injury was more likely to decrease attack rates in lodgepole pines. In lodgepole pine, attacks were initially concentrated on fire-injured trees, but during subsequent years beetles attacked substantial numbers of uninjured trees. In ponderosa pine, attacks were primarily on injured trees each year, although these stands were more heavily burned and had few uninjured trees. In total, 46% of all lodgepole and 56% of ponderosa pines underwent some degree of attack. Adult brood emergence within caged bole sections decreased with increasing bole char in lodgepole pine but increased in ponderosa pine, however these relationships did not scale to whole trees. Mountain pine beetle populations in both tree species four years post-fire were substantially lower than the year after fire, and wildfire did not result in population outbreaks.

Structure of Phoretic Mite Assemblages Across Subcortical Beetle Species at a Regional Scale.

Mites associated with subcortical beetles feed and reproduce within habitats transformed by tree-killing herbivores. Mites lack the ability to independently disperse among these habitats, and thus have evolved characteristics that facilitate using insects as transport between resources. Studies on associations between mites and beetles have historically been beetle-centric, where an assemblage of mite species is characterized on a single beetle species. However, available evidence suggests there may be substantial overlap among mite species on various species of beetles utilizing similar host trees. We assessed the mite communities of multiple beetle species attracted to baited funnel traps in Pinus stands in southern Wisconsin, northern Arizona, and northern Georgia to better characterize mite dispersal and the formation of mite-beetle phoretic associations at multiple scales. We identified approximately 21 mite species totaling 10,575 individuals on 36 beetle species totaling 983 beetles. Of the mites collected, 97% were represented by eight species. Many species of mites were common across beetle species, likely owing to these beetles' common association with trees in the genus Pinus. Most mite species were found on at least three beetle species. Histiostoma spp., Iponemus confusus Lindquist, Histiogaster arborsignis Woodring and Trichouropoda australis Hirschmann were each found on at least seven species of beetles. While beetles had largely similar mite membership, the abundances of individual mite species were highly variable among beetle species within each sampling region. Phoretic mite communities also varied within beetle species between regions, notably for Ips pini (Say) and Ips grandicollis (Eichhoff).

Do Phoretic Mites Influence the Reproductive Success of Ips grandicollis (Coleoptera: Curculionidae)?

Ips grandicollis (Eichhoff) can be an important pest of plantation trees in the Great Lakes region. Mites commonly occur in phoretic association with this beetle, but little is known about their effects on beetle population dynamics. We assessed the effects of phoretic mites on the reproductive success of I. grandicollis using complementary correlative and manipulative approaches. First, we allowed beetles to colonize Pinus resinosa (Ait) logs from sites across Wisconsin, reared them in a common environment, and related the species identities and abundances of mites with beetle production from each log. We found a positive relationship between I. grandicollis abundance and the presence of five mite species, Histiostoma spp., Dendrolaelaps quadrisetus (Berlese), Iponemus confusus (Lindquist), Trichouropoda australis Hirschmann, and Tarsonemus spp. While the abundance of individual mite species was positively correlated with beetle abundance, assessments of mite community structure did not explain beetle reproduction. Next, we introduced beetles that either had a natural complement of mites or whose mites were mechanically reduced into logs, and compared reproductive success between these beetles. We found no difference in colonization rates or beetle emergence between mite-present and mite-reduced treatments. Collectively, these results suggest a correlative, rather than causal, link between beetle reproductive success and mite incidence and abundances. These mites and beetles likely benefit from mutually suitable environments rather than exerting strong reciprocal impacts. Although mites may have some effects on I. grandicollis reproductive success, they likely play a minimal role compared to factors such as tree quality, beetle predation, and weather.

Evaluating Predators and Competitors in Wisconsin Red Pine Forests for Attraction to Mountain Pine Beetle Pheromones for Anticipatory Biological Control.

Mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae), is an irruptive tree-killing species native to pine forests of western North America. Two potential pathways of spread to eastern forests have recently been identified. First, warming temperatures have driven range expansion from British Columbia into Albertan jack pine forests that are contiguous with the Great Lakes region. Second, high temperatures and drought have fostered largescale outbreaks within the historical range, creating economic incentives to salvage killed timber by transporting logs to midwestern markets, which risks accidental introduction. We evaluated the extent to which local predators and competitors that exploit bark beetle semiochemicals would respond to D. ponderosae in Wisconsin. We emulated D. ponderosae attack by deploying lures containing synthetic aggregation pheromones with and without host tree compounds and blank control traps in six red pine plantations over 2 yr. Predator populations were high in these stands, as evidenced by catches in positive control traps, baited with pheromones of local bark beetles and were deployed distant from behavioral choice plots. Only one predator, Thanasimus dubius F. (Coleoptera: Cleridae) was attracted to D. ponderosae's aggregation pheromones relative to blank controls, and its attraction was relatively weak. The most common bark beetles attracted to these pheromones were lower stem and root colonizers, which likely would facilitate rather than compete with D. ponderosae. There was some, but weak, attraction of potentially competing Ips species. Other factors that might influence natural enemy impacts on D. ponderosae in midwestern forests, such as phenological synchrony and exploitation of male-produced pheromones, are discussed.

Foliar bacterial communities of trembling aspen in a common garden.

Microbial associations with plants are widely distributed and are structured by a number of biotic and physical factors. Among biotic factors, the host plant genotype may be integral to these plant-microbe interactions. Trees in the genus Populus have become models for studies in scaling effects of host plant genetics and in plant-microbe interactions. Using 454 pyrosequencing of the 16S rRNA gene, we assessed the foliar bacterial community of 7 genotypes of mature trembling aspen trees (Populus tremuloides Michx.) grown in a common garden. Trees were selected based on prior analyses showing clonal variation in their concentration of chemicals conferring resistance against insect herbivores. At broad taxonomic designations, the bacterial community of trembling aspen was similar across all plant genotypes. At a finer taxonomic scale, the foliage of these trees varied in their community composition, but there was no distinct pattern to colonization or abundance related to plant genotype. The most abundant operational taxonomic units (OTUs) were classified as Ralstonia, Bradyrhizobium, Pseudomonas, and Brucella. These OTUs varied across the common garden, but there was no significant effect of host plant genotype or spatial position on the abundance of these members. Our results suggest that aspen genotype is less important in the structuring of its foliar bacterial communities than are other, poorly understood processes.

Community composition and phenology of native Siricidae (Hymenoptera) attracted to semiochemicals in Minnesota.

As a result of the introduction of Sirex noctilio F. into North America, there has been increased interest in the poorly-described native Siricidae communities. To date, few studies have surveyed specifically for Siricidae, and many reports of native siricid populations are byproducts of sampling efforts targeting Coleoptera. We report results from a survey targeted specifically at native and exotic Siricidae in Minnesota. We used Lindgren funnel traps from 2006 to 2008 baited with α/ß-pinene (Sirex lure), ethanol (EtOH), EtOH + α-pinene, or Ips 3-part lures. We captured 704 native Siricidae comprising seven species, of which none were exotic. To our knowledge, this is one of the largest field collections of Siricidae from a single discrete set of localities in existence. Adult Siricidae began flying in June and continued into October each year. The α/ß-pinene lure was most effective, but the EtOH + α-pinene lure was also moderately effective. We compare our data with those from several states and provinces in the Great Lakes Region of North America. Our data provide insight into the community composition of native Siricidae in Minnesota, while concurrently providing evidence that S. noctilio populations have not yet reached this far into the continental United States.