Major Depressive Disorder is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus, GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+)-GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Lastly, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of effects of ketamine. Importantly, these effects occurred without altered activity of the mTOR pathway, nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus, enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical endpoints of rapidly acting antidepressants.

Earthquakes are caused by the release of tectonic strain accumulated between events. Recent advances in satellite geodesy mean we can now measure this interseismic strain accumulation with a high degree of accuracy. But it remains unclear how to interpret short-term geodetic observations, measured over decades, when estimating the seismic hazard of faults accumulating strain over centuries. Here, we show that strain accumulation rates calculated from geodetic measurements around a major transform fault are constant for its entire 250-year interseismic period, except in the ~10 years following an earthquake. The shear strain rate history requires a weak fault zone embedded within a strong lower crust with viscosity greater than ~1020 Pa s. The results support the notion that short-term geodetic observations can directly contribute to long-term seismic hazard assessment and suggest that lower-crustal viscosities derived from postseismic studies are not representative of the lower crust at all spatial and temporal scales.

Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.

The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is normally suppressed during pregnancy. Dysregulation of the HPA axis has been proposed to play a role in postpartum depression. However, direct investigation into the relationship between the HPA axis and postpartum depression has been hindered by the lack of useful animal models. Building on our discovery of a role for the K+/Cl-co-transporter, KCC2, in the GABAergic regulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN), critical for mounting the body's physiological response to stress, we assessed the role of KCC2 in the regulation of the HPA axis during pregnancy and the postpartum period. Here we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN. Mice lacking KCC2 specifically in corticosterone-releasing hormone (CRH) neurons, which govern the activity of the HPA axis (KCC2/Crh mice), exhibit dysregulation of the HPA axis and abnormal postpartum behaviors. Loss of KCC2 specifically in CRH neurons in the PVN is sufficient to reproduce the depression-like phenotype and deficits in maternal behaviors during the postpartum period. Similarly, chemogenetic activation of CRH neurons in the PVN is sufficient to induce abnormal postpartum behaviors and chemogenetic silencing of CRH neurons in the PVN can ameliorate abnormal postpartum behaviors observed in KCC2/Crh mice. This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression.

Land subsidence in urban environments is an increasingly prominent aspect in the monitoring and maintenance of urban infrastructures. In this study we update the subsidence information over Rome and its surroundings (already the subject of past research with other sensors) for the first time using Copernicus Sentinel-1 data and open source tools. With this aim, we have developed a fully automatic processing chain for land deformation monitoring using the European Space Agency (ESA) SentiNel Application Platform (SNAP) and Stanford Method for Persistent Scatterers (StaMPS). We have applied this automatic processing chain to more than 160 Sentinel-1A images over ascending and descending orbits to depict primarily the Line-Of-Sight ground deformation rates. Results of both geometries were then combined to compute the actual vertical motion component, which resulted in more than 2 million point targets, over their common area. Deformation measurements are in agreement with past studies over the city of Rome, identifying main subsidence areas in: (i) Fiumicino; (ii) along the Tiber River; (iii) Ostia and coastal area; (iv) Ostiense quarter; and (v) Tivoli area. Finally, post-processing of Persistent Scatterer Inteferometry (PSI) results, in a Geographical Information System (GIS) environment, for the extraction of ground displacements on urban infrastructures (including road networks, buildings and bridges) is considered.

SUMMARY We consider the viscoelastic rheology of the solid Earth under the Antarctic Peninsula due to ice mass loss that commenced after the breakup of the Larsen-B ice shelf. We extend the previous analysis of nearby continuous GPS time-series to include five additional years and the additional consideration of the horizontal components of deformation. They show strong uplift from ∼2002 to 2011 followed by reduced uplift rates to 2018. Modelling the GPS-derived uplift as a viscoelastic response to ongoing regional ice unloading from a new ice model confirms earlier estimates of low upper-mantle viscosities of ∼0.3–3 × 1018 Pa s in this region but allows a wide range of elastic lithosphere thickness. The observed and modelled north coordinate component shows little nonlinear variation due to the location of ice mass change to the east of the GPS sites. However, comparison of the observed and modelled east coordinate component constrains the upper-mantle viscosity to be less than ∼9 × 1018 Pa s, consistent with the viscosity range suggested by the uplift rates alone and providing important, largely independent, confirmation of that result. Our horizontal analysis showed only marginal sensitivity to modelled lithospheric thickness. The results for the horizontal components are sensitive to the adopted plate rotation model, with the estimate based on ITRF2014 suggesting that the sum of residual plate motion and pre-2002 glacial isostatic adjustment is likely less than ∼±0.5 mm yr−1 in the east component.

Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.

A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function.