Faculty Bibliography

Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this problem, we slightly modified previous methods and show robust seizures are common and frequent in both male and female mice. We employed continuous wideband video-EEG monitoring from 4 recording sites to best demonstrate the seizures. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 s) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE. SIGNIFICANCE: Although the IHKA model has been widely used in mice for epilepsy research, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent convulsive seizures that are robust, meaning they are >10 s and associated with complex high frequency rhythmic activity recorded from 2 hippocampal and 2 cortical sites. Seizure onset patterns usually matched the low-voltage fast and hypersynchronous seizures in TLE. Importantly, there is low mortality, and both sexes can be used. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression, and other topics of broad interest to the epilepsy research community. Finally, the results have implications for preclinical drug screening because seizure frequency increased in approximately half of the mice after a 6 wk. interval, suggesting that the typical 2 wk. period for monitoring seizure frequency is insufficient.

Efference copies of movement-inducing neural signals have been proposed to serve a role in gaze stabilization. Prior work has demonstrated a spino-extraocular motor circuit in the tadpole that relays copies of spinal commands to extraocular motor neurons. A recent study demonstrates the presence of this circuitry in mice, suggesting a unique method of gaze stabilization in the locomoting mouse.

The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.

The brain must extract behaviorally relevant latent variables from the signals streamed by the sensory organs. Such latent variables are often encoded in the dynamics that generated the signal rather than in the specific realization of the waveform. Therefore, one problem faced by the brain is to segment time series based on underlying dynamics. We present two algorithms for performing this segmentation task that are biologically plausible, which we define as acting in a streaming setting and all learning rules being local. One algorithm is model based and can be derived from an optimization problem involving a mixture of autoregressive processes. This algorithm relies on feedback in the form of a prediction error and can also be used for forecasting future samples. In some brain regions, such as the retina, the feedback connections necessary to use the prediction error for learning are absent. For this case, we propose a second, model-free algorithm that uses a running estimate of the autocorrelation structure of the signal to perform the segmentation. We show that both algorithms do well when tasked with segmenting signals drawn from autoregressive models with piecewise-constant parameters. In particular, the segmentation accuracy is similar to that obtained from oracle-like methods in which the ground-truth parameters of the autoregressive models are known. We also test our methods on data sets generated by alternating snippets of voice recordings. We provide implementations of our algorithms at https://github.com/ttesileanu/bio-time-series.

Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium - a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs non-canonically i.e., independent of hedgehog signaling. Gli1 and Dhh also have non-redundant activities. Unlike Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, non-autonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves.SIGNIFICANCE STATEMENTPeripheral nerves are organized into distinct cellular/ECM compartments: the epineurium, perineurium and endoneurium. This organization, with its associated cellular constituents, are critical for the structural and metabolic support of nerves and their response to injury. Here, we show Gli1 - a transcription factor normally expressed downstream of hedgehog signaling - is required for the proper organization of the endoneurium but not the perineurium. Unexpectedly, Gli1 expression by endoneurial cells is independent of, and functions non-redundantly with, Schwann Cell-derived Desert Hedgehog in regulating peripheral nerve architecture. These results further delineate how peripheral nerves acquire their distinctive organization during normal development and highlight mechanisms that may regulate their reorganization in pathologic settings including peripheral neuropathies and nerve injury.

Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally-restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.

BACKGROUND:Smoking cessation is the most effective means of slowing the decline of lung function associated with chronic obstructive pulmonary disease (COPD). While effective smoking cessation treatments are available, they are underutilized and nearly half of people with COPD continue to smoke. By addressing both nicotine and behavioral dependence, electronic cigarettes (EC) could help people with COPD reduce the harm of combustible cigarettes (CC) through reductions in number of Cigarettes per Day (CPD) or quitting CC completely. The purpose of this pilot study is to identify barriers and facilitators to the use of and assess the preliminary effectiveness of EC as a harm reduction strategy among people with COPD. METHODS:In an open-label two-arm randomized controlled trial pilot study, 60 patients identified as smokers with a COPD diagnosis via electronic health records from a large urban health center are randomized in a 1:1 ratio to either standard care [counseling + nicotine replacement therapy (NRT)] or counseling + EC. The NRT arm will receive nicotine patches and nicotine lozenges for 12 weeks. The EC arm will receive EC for 12 weeks. Both cohorts will receive counseling from a licensed mental health counselor. Using ecological momentary assessment, participants will report their use of CC in both arms and EC use in the EC arm daily via text message. Primary outcomes will be feasibility and acceptability of intervention, and secondary outcomes will be reduction in CPD and change in COPD symptoms as measured by COPD Assessment Tool (CAT) score at 12-weeks. EC displacement of CC. To explore attitudes towards the use of EC as a harm-reduction strategy for patients with COPD, interviews will be performed with a sample of participants from both study arms. DISCUSSION/CONCLUSIONS:Despite decades of availability of smoking cessation medications, nearly half of people with COPD still smoke. This study aims to address the unmet need for feasible and effective strategies for reducing CC use among those with COPD, which has the potential to significantly improve the health of people with COPD who smoke. Trial Registration ClinicalTrials.gov Identifier: NCT04465318.

By linking the past with the future, our memories define our sense of identity. Because human memory engages the conscious realm, its examination has historically been approached from language and introspection and proceeded largely along separate parallel paths in humans and other animals. Here, we first highlight the achievements and limitations of this mind-based approach and make the case for a new brain-based understanding of declarative memory with a focus on hippocampal physiology. Next, we discuss the interleaved nature and common physiological mechanisms of navigation in real and mental spacetime. We suggest that a distinguishing feature of memory types is whether they subserve actions for single or multiple uses. Finally, in contrast to the persisting view of the mind as a highly plastic blank slate ready for the world to make its imprint, we hypothesize that neuronal networks are endowed with a reservoir of neural trajectories, and the challenge faced by the brain is how to select and match preexisting neuronal trajectories with events in the world.

When it comes to detecting volatile chemicals, biological olfactory systems far outperform all artificial chemical detection devices in their versatility, speed, and specificity. Consequently, the use of trained animals for chemical detection in security, defense, healthcare, agriculture, and other applications has grown astronomically. However, the use of animals in this capacity requires extensive training and behavior-based communication. Here we propose an alternative strategy, a bio-electronic nose, that capitalizes on the superior capability of the mammalian olfactory system, but bypasses behavioral output by reading olfactory information directly from the brain. We engineered a brain-computer interface that captures neuronal signals from an early stage of olfactory processing in awake mice combined with machine learning techniques to form a sensitive and selective chemical detector. We chronically implanted a grid electrode array on the surface of the mouse olfactory bulb and systematically recorded responses to a large battery of odorants and odorant mixtures across a wide range of concentrations. The bio-electronic nose has a comparable sensitivity to the trained animal and can detect odors on a variable background. We also introduce a novel genetic engineering approach that modifies the relative abundance of particular olfactory receptors in order to improve the sensitivity of our bio-electronic nose for specific chemical targets. Our recordings were stable over months, providing evidence for robust and stable decoding over time. The system also works in freely moving animals, allowing chemical detection to occur in real-world environments. Our bio-electronic nose outperforms current methods in terms of its stability, specificity, and versatility, setting a new standard for chemical detection.