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Graduate School of Biomedical Sciences

The Jamie Maguire Lab

GABAergic Control of the Body’s Stress Response

Stress negatively impacts health, triggering or worsening conditions ranging from the common cold to cancer. The Maguire lab seeks to understand how the body’s physiological response to stress is regulated and how we can prevent the adverse effects of stress on overall health. The body’s response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, which is governed by corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. The activity of CRH neurons is tightly regulated by GABAergic inhibition. Our goal is to understand the role of the GABAergic control of the HPA axis under physiological conditions and how this system becomes dysregulated and contributes to neurological and neuropsychiatric diseases.

GABAergic Regulation of the HPA Axis in Postpartum Depression

Nearly 20% of mothers suffer from postpartum depression, however, research into the pathophysiology of postpartum depression has been largely impeded by the lack of useful animal models of such a complex disorder. Our research program aims to elucidate the mechanisms underlying postpartum depression using two unique mouse models identified by our laboratory. We are testing the novel hypothesis that deficits in GABAergic regulation of corticotropin-releasing hormone (CRH) neurons results in dysregulation of the HPA axis during the peripartum period that, in turn, leads to abnormal postpartum behaviors using genetic, optogenetic, and chemogenetic techniques.

Maguire Fig 1

Figure 1. Chemogenetic modulation of CRH neurons in the PVN alters postpartum behaviors. a, A representative image demonstrating colocalization of DREADD expression (mCherry, red) with the endogenous CRH peptide (AlexaFluor-488, green). b, Representative electrophysiological recordings demonstrating the effect of CNO administration on the firing rate and RMP of CRH neurons from Gq DREADD and Gi DREADD mice. Silencing of CRH neurons in the PVN of KCC2/Crh mice increases the latency to the first bout of immobility (c) and decreases the total time spent immobile in the forced swim test (d) compared to KCC2/Crh AAV-GFP controls (n = 8–14 mice per experimental group; * denotes p < 0.05 using a Student’s t-test). KCC2/Crh dams expressing Gi DREADDs exhibit a decreased latency to approach their pups (e) and spend more time interacting with their pups (f) in the maternal approach test (n = 8–18 mice per experimental group; * denotes p<0.05 using a Student’s t-test).

GABAergic Control of the HPA Axis in the Co-morbidity of Depression and Epilepsy

The Maguire Lab is investigating the role of HPA axis in the co-morbidity of depression and epilepsy. Stress is a trigger for seizures in patients with epilepsy and hypercortisolism is a hallmark feature of depression, leading us to hypothesize that the HPA axis may play a role in co-morbidity of epilepsy and depression. Our lab recently discovered that seizures activate the HPA axis, creating a proconvulsant environment fostering further seizure susceptibility and increasing depression-like behaviors in chronically epileptic mice. We are employing genetic and chemogenetic approaches to investigate the role of HPA axis dysfunction in negative epilepsy outcomes.

Maguire Fig 2

Figure 2. Decreased seizure susceptibility in Gabrd/Crh mice. a) Representative electrographic epileptiform activity over the 2 hr recording period in Gabrd/Crh mice and Cre-/- littermates and Gabrd/Crh mice treated with exogenous corticosterone. b, The average latency to the onset of the first electrographic seizure in Gabrd/Crh mice, Cre-/- littermates, and Gabrd/Crh mice treated with exogenous corticosterone. c, The average percent time exhibiting epileptiform activity in Gabrd/Crh mice, Cre-/- littermates, and Gabrd/Crh mice treated with exogenous corticosterone. n = 7 - 8 mice per experimental group; * denotes p<0.05 using a one-way ANOVA.

GABAergic Signaling in the Network Communication of Anxiety

In collaboration with the Reijmers lab, we demonstrated a critical role for parvalbumin-positive (PV) interneurons in the network communication of fear and anxiety. Specifically, PV interneurons in the basolateral amygdala (BLA) are required for the network communication of safety and chemogenetic silencing of PV interneurons facilitates the network communication of fear. Our laboratory is building on this discovery to investigate the role of PV interneurons in the BLA in mediating the anxiolytic effects of alcohol and whether the loss of PV interneurons in the BLA contributes to co-morbid anxiety in epilepsy.

Maguire Fig 3

Figure 3. BLA PV-interneurons control the balance between two functionally opposed low frequency oscillations. a) Example full trial spectrograms from a single animal demonstrating an a 3-6Hz oscillation during freezing (red boxes), as well as a shift towards increased 3-6Hz power compared to 6-12Hz power caused by silencing BLA PV interneurons. “freezing” here denotes periods of >50% freezing per bin. b-e) Silencing PV-interneurons during post-extinction retrieval leads to an increase in freezing in the conditioned context, an increase in 3-6Hz power in BLA, decrease 6-12Hz power, and an increase in 3-6/6-12 Hz BLA power ratio (n = 11 mice, paired t-tests). Scatter plot: Normalized BLA power ratio correlated with post-extinction freezing in CNO-injected mice (n = 11 mice, linear regression, R2 = 0.48). *P < 0.05, **P < 0.01. Bar graphs: mean ± SEM.

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