Biology subjects

Maguire, J.

Publications and source records attributed to Maguire, J..

29 records · Page 2Linked to original sources

bioRxiv2023

Network States in the Basolateral Amygdala Predicts Voluntary Alcohol Consumption

Although most adults in the United States will drink alcohol in their life, only about 6% will go on to develop an alcohol use disorder (AUD). While a great deal of work has furthered our understanding of the cycle of addiction, it remains unclear why certain people transition to disordered drinking. Altered activity in regions implicated in AUDs, like the basolateral amygdala (BLA), has been suggested to play a role in the pathophysiology of AUDs, but how these networks contribute to alcohol misuse remains unclear. Our recent work demonstrated that alcohol can modulate BLA network states and that GABAergic parvalbumin (PV) interneurons are crucial modulators of network activity in the BLA. Further, our lab has demonstrated that {delta} subunit-containing GABAA receptors, which are modulated by alcohol, are highly expressed on PV interneurons in the BLA. These receptors on PV interneurons have also been shown to influence alcohol intake in a voluntary binge drinking paradigm and anxiety-like behavior in withdrawal. Therefore, we hypothesized that alcohol may impact BLA network states via {delta} subunit-containing GABAA receptors on PV interneurons to impact the extent of alcohol use. To test this hypothesis, we measured the impact of acute alcohol exposure on oscillatory states in the basolateral amygdala and then assessed the relationship to the extent of voluntary ethanol consumption in the Intermittent Access, Drinking-in-the-Dark-Multiple Scheduled Access, and Chronic Intermittent Ethanol exposure paradigms. Remarkably, we demonstrate that the average alcohol intake negatively correlates with {delta} subunit-containing GABAA receptor expression on PV interneurons and gamma power in the BLA after the first exposure to alcohol. These data implicate {delta} subunit-containing GABAA receptor expression on PV interneurons in the BLA in voluntary alcohol intake and suggest that BLA network states may serve as a useful biomarker for those at risk for alcohol misuse. Significance StatementOscillatory states in the BLA have been demonstrated to drive behavioral states involved in emotional processing, including negative valence processing. Given that negative emotional states/hyperkatifeia contribute to the cycle of AUDs, our previous work demonstrating the ability of alcohol to modulate BLA network states and thereby behavioral states suggests that this mechanism may influence alcohol intake. Here we demonstrate a relationship between the ability of alcohol to modulate oscillations in the BLA and future alcohol intake such that the extent to which alcohol influences BLA network states predict the extent of future voluntary alcohol intake. These findings suggest that individual variability in the sensitivity of the BLA network to alcohol influences voluntary alcohol consumption.

neuroscience↗

bioRxiv2022

Semaphorin 4D induced inhibitory synaptogenesis restores benzodiazepine sensitivity in a mouse model of Status Epilepticus

Previously we demonstrated that intra-hippocampal infusion of purified, Semaphorin 4D (Sema4D) extracellular domain into the mouse hippocampus rapidly promotes formation of GABAergic synapses and decreases seizure susceptibility in mice. Given the relatively fast action of Sema4D treatment revealed by these studies, we sought to determine the time course of Sema4D treatment on hippocampal network activity using an acute hippocampal slice preparation. We performed long-term extracellular recordings from area CA1 encompassing a 2 hour application of Sema4D and found that hippocampal excitation is suppressed hours following treatment. We also asked if Sema4D treatment could ameliorate seizures in an acute seizure model: the kainic acid (KA) mouse model of Status Epilepticus (SE). We demonstrate that Sema4D treatment suppresses seizures and lessens benzodiazepine (BZD) insensitivity which is a hallmark of refractory SE. Lastly, we sought to explore alternative methods of Sema4D delivery to hippocampus and thus created an Adeno Associated Virus expressing the extracellular domain of Sema4D. Our data reveal that virally delivered, chronically overexpressed Sema4D extracellular domain promotes GABAergic synapse formation and suppresses seizure activity similar to the actions of purified Sema4D protein. These results provide proof of concept that Sema4D-mediated GABAergic synapse development could combat BZD insensitivity in intractable forms of epilepsy, and that viral delivery of Sema4D is an efficacious and promising delivery method.

neuroscience↗

bioRxiv2022

Hypothalamic-pituitary-adrenal axis dysfunction worsens epilepsy outcomes and increases SUDEP risk

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger both epilepsy and depression and significant accumulating evidence, from both human and animal studies, support that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to the comorbidity of these two disorders1. Here we directly investigate the contribution of HPA axis dysfunction to epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (KCC2/Crh mice) that lacks the K+/Cl- co-transporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced hyperactivation of the HPA axis.2,3 Here we demonstrate that HPA axis dysfunction in KCC2/Crh mice is associated with increased vulnerability to behavioral deficits in chronically epileptic mice and more severe neuropathological features associated with chronic epilepsy (e.g. increased mossy fiber sprouting). Despite equivalent seizure burden, HPA axis dysfunction in these chronically epileptic mice increased the incidence of sudden unexpected death in epilepsy (SUDEP). Suppressing HPA axis hyperexcitability in this model using a pharmacological or chemogenetic approach decreased SUDEP incidence, supporting HPA axis dysfunction in SUDEP vulnerability. We also observed changes in neuroendocrine markers in individuals that died of SUDEP compared to people with epilepsy or individuals without a history of epilepsy. Together, these findings describe a novel, nongenetic mouse model of SUDEP which will benefit preclinical SUDEP research to gain a better understanding of the underlying pathological mechanisms contributing to SUDEP. HPA axis dysfunction increases vulnerability to psychiatric comorbidities in epilepsy and may be a risk factor for SUDEP.

neuroscience↗

bioRxiv2022

Sex differences in the alcohol-mediated modulation of BLA network states

About 85% of adults in the United States report drinking alcohol in their lifetime. Mood disorders, like generalized anxiety disorder and major depression, are highly comorbid with alcohol use. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, modulation of BLA network/oscillatory states via parvalbumin-positive (PV) GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety. Further, PV interneurons express a high density of {delta}-subunit-containing GABAA receptors (GABAARs), which are sensitive to low concentrations of alcohol. Our lab previously demonstrated that {delta}-subunit-containing GABAARs on PV interneurons in the BLA influence voluntary ethanol intake and anxiety-like behavior in withdrawal. Therefore, we hypothesized that the effects of alcohol may modulate BLA network states that have been associated with fear and anxiety behaviors via {delta}-GABAARs on PV interneurons in the BLA. Given the impact of ovarian hormones on the expression of {delta}-GABAARs, we examined the ability of alcohol to modulate local field potentials (LFPs) in the BLA from male and female C57BL/6J and Gabrd-/- mice after acute and repeated exposure to alcohol. Here, we demonstrate that acute and repeated alcohol can differentially modulate oscillatory states in male and female C57BL/6J mice, a process which involves {delta}-GABAARs. This is the first study to demonstrate that alcohol is capable of altering network states implicated in both anxiety and alcohol use disorders. Significance StatementAlcohol use disorder and mood disorders are highly comorbid. The basolateral amygdala (BLA) is implicated in both of these disorders, but the mechanisms contributing to their shared pathophysiology remain uncertain. Here we demonstrate that acute and repeated alcohol exposure can alter network oscillations in the BLA which control the behavioral expression of fear and anxiety. These data suggest that alcohol may directly influence network states associated with mood. Further, we demonstrate sex differences in alcohols ability to modulate BLA network states, an effect involving {delta}-GABAA receptors, which may contribute to sex differences in alcohol intake and comorbid mood disorders. These data potentially point to a novel mechanism mediating the effects of alcohol on affective states. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2022

Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress

Chronic stress is a major risk factor for psychiatric illnesses, including depression; however, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. The recent FDA approval of antidepressants with novel mechanisms of action, like Zulresso(R), a synthetic neuroactive steroid analog with molecular pharmacology similar to allopregnanolone, has spurred interest in new therapeutic targets and, potentially, novel pathophysiological mechanisms for depression. Allopregnanolone acts as a positive allosteric modulator of GABAA receptors (GABAARS), acting preferentially at {delta} subunit-containing receptors ({delta}-GABAARS). Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone and allopregnanolone analogs; however, the role of endogenous neurosteroids in the pathophysiology of depression remains unknown. Here, we examine whether altered neurosteroid signaling may contribute to behavioral deficits following chronic unpredictable stress (CUS) in mice. We first identified reductions in expression of {delta}-GABAARs, the predominant site of action of 5a-reduced neuroactive steroids, following CUS. Additionally, utilizing LC-MS/MS we discovered a decrease in levels of allopregnanolone in the BLA, but not plasma of mice following CUS, an indication of impaired neurosteroid synthesis. CRISPR knockdown the rate-limiting enzymes involved in allopregnanolone synthesis, 5-reductase type 1 and 2, in the BLA mimicked the behavioral deficits associated with CUS in mice. Furthermore, overexpression expression of 5-reductase type 1 and 2 in the BLA improved behavioral outcomes. Collectively, this suggests chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits similar to those observed following CUS. Further, these studies suggest that the therapeutic efficacy of allopregnanolone-based treatments may be due to their ability to directly target the underlying pathophysiology of mood disorders. Therefore, targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy for the treatment of mood disorders.

neuroscience↗

bioRxiv2021

Neuromodulation-induced burst firing in parvalbumin interneurons of the basolateral amygdala mediates transition between fear-associated network and behavioral states

Patterned coordination of network activity in the basolateral amygdala (BLA) is important for fear expression. Neuromodulatory systems play an essential role in regulating changes between behavioral states, however the mechanisms underlying the neuromodulatory control of BLA circuits that mediates transitions between brain and behavioral states remain largely unknown. We examined the role of neuromodulation of parvalbumin (PV)-expressing interneurons in the BLA in coordinating network and behavioral states using combined chemogenetics, ex vivo patch clamp recordings, and in vivo and ex vivo local field potential recordings. We show that Gq signaling, whether by the designer receptor, hM3D, 1A adrenoreceptors, or 5-HT2a serotonergic receptors, induces a previously undescribed, highly stereotyped bursting pattern of activity in BLA PV interneurons that generates synchronous bursts of inhibitory postsynaptic currents and phasic firing in the BLA principal neurons. The Gq activation in PV interneurons induced a transition from tonic to phasic firing in the BLA PV neurons and principal neurons and suppressed BLA gamma oscillations in slices and suppressed BLA gamma and potentiated theta power in vivo. Gq activation in BLA PV interneurons also facilitated fear memory recall, consistent with previous reports of BLA gamma suppression and theta potentiation during conditioned fear expression. Thus, our data reveal a BLA parvalbumin neuron-specific Gq neuromodulatory mechanism that mediates the transition to a fear-associated network and behavioral state.

neuroscience↗

bioRxiv2021

Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks

Each year vast international resources are wasted on irreproducible research. The scientific community has been slow to adopt standard software engineering practices, despite the increases in high-dimensional data, complexities of workflows, and computational environments. Here we show how scientific software applications can be created in a reproducible manner when simple design goals for reproducibility are met. We describe the implementation of a test server framework and 40 scientific benchmarks, covering numerous applications in Rosetta bio-macromolecular modeling. High performance computing cluster integration allows these benchmarks to run continuously and automatically. Detailed protocol captures are useful for developers and users of Rosetta and other macromolecular modeling tools. The framework and design concepts presented here are valuable for developers and users of any type of scientific software and for the scientific community to create reproducible methods. Specific examples highlight the utility of this framework and the comprehensive documentation illustrates the ease of adding new tests in a matter of hours.

bioinformatics↗

bioRxiv2020

Colonization with the commensal fungus Candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling

Anxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7% of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. We used a mouse model of gastrointestinal (GI) colonization to demonstrate that the commensal fungus Candida albicans affects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized with C. albicans demonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid anandamide (AEA). C. albicans-colonized mice exhibited systemic changes in the endocannabinoidome, within the GI tract and the brain, and showed a negative correlation between brain AEA levels and serum CORT. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.

microbiology↗

bioRxiv2020

Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress

Ras-GRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates Ras and Rac GTPases. In hippocampal neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed that GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after exposure to 7-days of restraint-stress (7DRS) (30 min/day) elevation of serum CORT levels are suppressed in early adolescent (EA) female, but not EA male or adult female GRF1 knockdown mice. Here, we show that this phenotype is due, at least in part, to the loss of GRF1 expression in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockdown specifically in these cells also reduces serum CORT response to 7DRS in EA females, but not EA males or adult females. Moreover, it reduces females CORT levels to those to found in comparably stressed control male mice. GRF1 knockdown in CRF cells also blocks the anxiolytic phenotype normally found in EA females 24 hrs after 7DRS. Interestingly, loss of GRF1 in these cells has no effect after only 3 exposures to restraint stress, revealing a role for GRF1 in repeated stress-induced CRF cell plasticity that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response early-adolescent female display to repeated stress.

neuroscience↗

bioRxiv2019

Efficient chromosome-scale haplotype-resolved assembly of human genomes

Haplotype-resolved or phased sequence assembly provides a complete picture of genomes and complex genetic variations. However, current phased assembly algorithms either fail to generate chromosome-scale phasing or require pedigree information, which limits their application. We present a method that leverages long accurate reads and long-range conformation data for single individuals to generate chromosome-scale phased assembly within a day. Applied to three public human genomes, PGP1, HG002 and NA12878, our method produced haplotype-resolved assemblies with contig NG50 up to 25 Mb and phased [~]99.5% of heterozygous sites to 98-99% accuracy, outperforming other approaches in terms of both contiguity and phasing completeness. We demonstrate the importance of chromosome-scale phased assemblies to discover structural variants (SVs), including thousands of new transposon insertions, and of highly polymorphic and medically important regions such as HLA and KIR. Our improved method will enable high-quality precision medicine and facilitate new studies of individual haplotype variation and population diversity.

bioinformatics↗

bioRxiv2016

Dynamics of the bacterial community associated with Phaeodactylum tricornutum cultures

The pennate diatom Phaeodactylum tricornutum is a model organism able to synthesise industrially-relevant molecules. Large-scale monocultures are prone to bio-contamination, however, little is known about the identity of the invading organisms. To gain insight into the bacterial community associated with diatoms, we translated the complexity of a natural system into reproducible experiments where we investigated the microbiome of P. tricornutum cultures. The results revealed a dynamic bacterial community that changed over time and in differing media conditions. We propose a network of putative interactions between P. tricornutum and the main bacterial factions, which is translated into a set of ordinary differential equations constituting a computational dynamic model. The proposed mathematical model is able to capture the population dynamics, further supporting the hypothesised interactions. The interdisciplinary approach implemented provides a framework for understanding the dynamics of diatom-associated microbial communities, and provides a foundation for further systematic investigations of host-microbe interactions.

ecology↗