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Summary From February 1994 to April 2000, 29 emergency gelfoam embolizations for spontaneous ruptured hepatocellular carcinoma (HCC) performed in 28 patients were retrospectively reviewed. There were 11 patients in Child's A , 11 in Child's B and six in Child's C classification of cirrhosis. The duration of the procedure, artery embolized and complications were reviewed, and the Child-Pugh classification of each patient was correlated with their mean survival period. Embolization was done in 12 right hepatic arteries, two left hepatic arteries and 15 proper hepatic arteries. In one patient, the left hepatic artery was embolized initially but the proper hepatic artery was also embolized because another subcapsular liver tumour was found after reviewing the preangiogram CT scan. The entire procedure took 40-170 min (mean = 86 min) with no periprocedural complication. Following embolization, the mean survival period for Child's A class was 218.3 days, Child's B class was 83.4 days and Child's C class was 11.0 days. Transcatheter embolization is an effective treatment to arrest bleeding in spontaneous ruptured HCC. Patients with Child's A class cirrhosis have the longest survival. Selective embolization of either the right or the left hepatic artery alone carries the potential risk of missing multifocal HCC that might not be easily appreciated during angiography. [ABSTRACT FROM AUTHOR]

As a crucial player in excitatory synaptic transmission, AMPA receptors (AMPARs) contribute to the formation, regulation, and expression of social behaviors. AMPAR modifications have been associated with naturalistic social behaviors, such as aggression, sociability, and social memory, but are also noted in brain diseases featuring impaired social behavior. Understanding the role of AMPARs in social behaviors is timely to reveal therapeutic targets for treating social impairment in disorders, such as autism spectrum disorder and schizophrenia. In this review, we will discuss the contribution of the molecular composition, function, and plasticity of AMPARs to social behaviors. The impact of targeting AMPARs in treating brain disorders will also be discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Larosa and Wong.)

Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies., (© 2024. The Author(s).)

Background/purpose: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes., Methods: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200., Results: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3., Conclusion: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

Lexical alignment, a communication phenomenon where conversational partners adapt their word choices to become more similar, plays an important role in the development of language and social communication skills. While this has been studied extensively in the conversations of preschool-aged children and their parents in Western, Educated, Industrialized, Rich, and Democratic (WEIRD) communities, research in other pediatric populations is sparse. This study makes significant expansions on the existing literature by focusing on alignment in naturalistic conversations of school-aged children from a non-WEIRD population across multiple conversational tasks and with different types of adult partners. Typically developing children aged 5 to 8 years (n = 45) engaged in four semi-structured conversations that differed by task (problem-solving vs. play-based) and by partner (parent vs. university student), resulting in a corpus of 180 conversations. Lexical alignment scores were calculated and compared to sham conversations, representing alignment occurring at the level of chance. Both children and adults coordinated their conversational utterances by re-using or aligning each other's word choices. This alignment behavior persisted across conversational tasks and partners, although the degree of alignment was moderated by the conversational context. These findings suggest that lexical alignment is a robust phenomenon in conversations between school-age children and adults. Furthermore, this study extends lexical alignment findings to a non-WEIRD culture, suggesting that alignment may be a coordination strategy employed by adults and children across diverse linguistic and cultural backgrounds., (© 2024 Cognitive Science Society LLC.)

This case series reports on two patients who developed macular holes while on prostaglandin analogs (PGA) therapy. The first case involves a 63-year-old woman with a history of a macular hole of the left eye that had spontaneously closed. After starting PGA therapy for elevated intraocular pressure, cystoid macular edema formed, which resulted in reopening of the macular hole. The second case involves a 64-year-old man with primary open-angle glaucoma, on PGA therapy, with a newly diagnosed small macular hole of the right eye that closed after cessation of the PGA therapy. These cases demonstrate an association between prostaglandin analogs and the formation or reopening of full-thickness macular holes. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:112-115.] .

Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia., Competing Interests: The authors declare no competing interests., (Copyright: © 2023 Rocchetti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90 , was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 ( NRG3 ) as one of the targets of SNORD90 , which we show is regulated through the accumulation of N 6 -methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission., Competing Interests: RL, AK, JL, JD, LF, JY, YB, ZA, PI, HM, TW, EI, CB, PB, FF, BF, RM, DM, SP, CS, RU, CN, NM, SK, AC, GT No competing interests declared, RL RM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Neomind, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF, JF JAF has received consulting and speaking fees from Takeda and RBH, and research funding from NSERC, CIHR, and OBI, (© 2023, Lin, Kos et al.)

Purpose: To evaluate the association of posterior vitreous opacities (PVOs) on optical coherence tomography with retinal tears identified on examination in patients with acute, symptomatic posterior vitreous detachment (PVD)., Methods: Data were retrospectively collected from the medical records of 388 patients with acute, symptomatic PVD between January 1, 2021, and June 30, 2021. Included patients had received a primary diagnosis of PVD and presented with flashes and/or floaters. Optical coherence tomography scans were reviewed by two separate readers for the presence of PVOs. The primary outcome was the presence of retinal tear on fundus photograph and on examination., Results: Of 388 patients who presented with acute PVD symptoms, 90 (23.2%) were found to have a retinal tear on dilated fundus examination. Among these patients, 78 (86.7%) were found to have PVOs on optical coherence tomography. Statistical analysis demonstrated a significant relationship between the presence of PVOs and retinal tear ( P < 0.01). The sensitivity and specificity of this finding was 86.7% and 72.5%, respectively. Further analysis included area under the curve from receiver operating characteristic curve which was found to be 0.80., Conclusion: The presence of PVOs on optical coherence tomography is suggestive of a retinal tear in patients with acute, symptomatic PVD.

Vestibular information processed first by the brainstem vestibular nucleus (VN), and further by cerebellum and thalamus, underlies diverse brain function. These include the righting reflexes and spatial cognitive behaviour. While the cerebellar and thalamic circuits that decode vestibular information are known, the importance of VN neurons and the temporal requirements for their maturation that allow developmental consolidation of the aforementioned circuits remains unclear. We show that timely unsilencing of glutamatergic circuits in the VN by NMDA receptor-mediated insertion of AMPAR receptor type 1 (GluA1) subunits is critical for maturation of VN and successful consolidation of higher circuits that process vestibular information. Delayed unsilencing of NMDA receptor-only synapses of neonatal VN neurons permanently decreased their functional connectivity with inferior olive circuits. This was accompanied by delayed pruning of the inferior olive inputs to Purkinje cells and permanent reduction in their plasticity. These derangements led to deficits in associated vestibular righting reflexes and motor co-ordination during voluntary movement. Vestibular-dependent recruitment of thalamic neurons was similarly reduced, resulting in permanently decreased efficiency of spatial navigation. The findings thus show that well-choreographed maturation of the nascent vestibular circuitry is prerequisite for functional integration of vestibular signals into ascending pathways for diverse vestibular-related behaviours., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ventral hippocampal (vHPC)-prefrontal cortical (PFC) pathway dysfunction is a core neuroimaging feature of schizophrenia. However, mechanisms underlying impaired connectivity within this pathway remain poorly understood. The vHPC has direct projections to the PFC that help shape its maturation. Here, we wanted to investigate the effects of early developmental vHPC perturbations on long-term functional PFC organization. Using whole-cell recordings to assess PFC cellular activity in transgenic male mouse lines, we show early developmental disconnection of vHPC inputs, by excitotoxic lesion or cell-specific ablations, impairs pyramidal cell firing output and produces a persistent increase in excitatory and decrease in inhibitory synaptic inputs onto pyramidal cells. We show this effect is specific to excitatory vHPC projection cell ablation. We further identify PV-interneurons as a source of deficit in inhibitory transmission. We find PV-interneurons are reduced in density, show a reduced ability to sustain high-frequency firing, and show deficits in excitatory inputs that emerge over time. We additionally show differences in vulnerabilities to early developmental vHPC disconnection, wherein PFC PV-interneurons but not pyramidal cells show deficits in NMDA receptor-mediated current. Our results highlight mechanisms by which the PFC adapts to early developmental vHPC perturbations, providing insights into schizophrenia circuit pathology., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding the individual variability that comes with the likelihood of developing stress-related psychopathologies is of paramount importance when addressing mechanisms of their neurobiology. This article focuses on the hippocampus as a region that is highly influenced by chronic stress exposure and that has strong ties to the development of related disorders, such as depression and post-traumatic stress disorder. We first outline three commonly used animal models that have been used to separate animals into susceptible and resilient cohorts. Next, we review molecular and functional hippocampal markers of susceptibility and resilience. We propose that the hippocampus plays a crucial role in the differences in the processing and storage of stress-related information in animals with different stress susceptibilities. These hippocampal markers not only help us attain a more comprehensive understanding of the various facets of stress-related pathophysiology, but also could be targeted for the development of new treatments., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is limited data on the presentation and surgical outcomes of idiopathic macular holes (IMH) for different ethnic and racial groups. Recognition of distinct, clinically-relevant patient subgroups may provide opportunities to identify specific unmet needs including possible barriers to optimal healthcare delivery. Medical records of patients who underwent surgery for IMH (between 2016 and 2022) at a large, urban retina practice were reviewed and self-reported ethnicity (Hispanic and non-Hispanic) and race (Asian, Black, White, and Other) were captured. The primary variables included (1) mean minimum linear diameter (MLD) at presentation and (2) surgical outcome (IMH closure status). Overall, mean MLD for all study eyes (515) was 366.1 μm, and surgical success was achieved in 489 (95.0%) eyes. Hispanic eyes presented with larger mean MLD (p = 0.002) compared to non-Hispanic eyes. Asian, Black, and Other eyes presented with larger mean MLD (p = 0.033, p < 0.001, p < 0.001) when compared to White eyes. The presentation of IMH varied in severity among different ethnic and racial groups. Hispanic patients were found to have worse preoperative visual acuity (VA), longer time to surgery, and larger mean MLD and BD compared to non-Hispanic participants. Black and Other patients were found to have worse VA, time to surgery, and larger mean MLD and BD when compared to White participants.

Herein are reported four eyes among three patients with favorable anti-vascular endothelial growth factor crunch syndrome by which contraction of fibrovascular tissue led to relief of vitreoretinal traction without surgical intervention. This phenomenon led to complete or partial retinal reattachment in two patients with diabetic tractional retinal detachments. These cases represent favorable anatomic outcomes of crunch syndrome secondary to anti-vascular endothelial growth factor pharmacotherapy and are unique compared with most cases, which have been associated with negative outcomes. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:455-459.] .

Purpose: To assess outcomes among eyes undergoing surgery for recurrent rhegmatogenous retinal detachment (RRD) and investigate variables that correlate with visual and anatomic outcomes., Design: Retrospective, consecutive case series., Participants: Eyes in which initial RRD repair failed that underwent ≥2 surgeries for RRD repair between January 1, 2016, and December 31, 2020., Methods: A retrospective analysis of eyes that underwent ≥2 RRD repairs. Eyes with etiologies of retinal detachment other than RRD, previous vitreoretinal surgery, and proliferative diabetic retinopathy were excluded. One-way analysis of variance with Tukey honestly significant difference testing and multivariate regression analyses were used to assess statistical significance., Main Outcome Measures: Anatomic success rate and habitual best recorded visual acuity (VA) at postoperative time intervals and at final follow-up., Results: The single-operation success rate (SOSR) among eyes that underwent primary RRD repair over a 5-year period was 92.4% (2021 of 2187 eyes). The remaining 166 eyes (164 patients) in which primary RRD repair failed were included in this study. Although the anatomic success rates after the second and third RRD repairs were lower than the SOSR (71.7% and 68.1%, respectively), the final anatomic success rates did not significantly differ between eyes that underwent ≥2 RRD repairs (range, 90.6%-100%) (P > 0.05), and final anatomic success was achieved in 95.8% of the eyes. The average VA at both postoperative time intervals and final follow-up decreased with an increased total number of RRD repairs. Eyes that received silicone oil endotamponade during the second RRD repair were 20.3% (P = 0.03) and 38.4% (P = 0.04) less likely to require a third RRD repair compared with eyes that received octafluoropropane and sulfur hexafluoride gases, respectively. Eyes that developed a third RRD due to proliferative vitreoretinopathy (PVR) (n = 43) were 110% more likely to require a fourth RRD repair than eyes that developed a third RRD due to a new tear or failure to reattach (n = 4) (P = 0.04)., Conclusions: In this series, the rates of anatomic success appeared consistent after each surgery when multiple reoperations were required for RRD. The VA decreased with an increased total number of RRD repairs, and the endotamponade choice might have affected the risk of additional reoperations. Proliferative vitreoretinopathy was a significant prognostic factor for RRD recurrence., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A pertinent mechanism by which stress impacts learning and memory is through stress-induced plastic changes in glutamatergic transmission in the hippocampus. For instance, acute stress has been shown to alter the expression, binding, and function of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR). However, the consequences of chronic stress, which could lead to various stress-related brain disorders, on NMDAR function remain unclear. While most studies on NMDARs focused on these receptors in synapses (synaptic NMDARs or sNMDARs), emerging findings have revealed functional roles of NMDARs outside synapses (extrasynaptic NMDARs or exNMDARs) that are distinct from those of sNMDARs. Using a restraint stress paradigm in adult rats, the objective of the current study is to examine whether sNMDARs and exNMDARs in the hippocampus are differentially regulated by acute and chronic stress. We examined sNMDAR and exNMDAR function in dorsal CA1 hippocampal neurons from brain slices of adult rats that were acutely (1 episode) or chronically (21 daily episodes) stressed by restraint (30 min). We found that acute stress increases sNMDAR but suppresses exNMDAR function. Surprisingly, we only observed a reduction in exNMDAR function after chronic stress. Taken together, our findings suggest that sNMDARs and exNMDARs may be differentially regulated by acute and chronic stress. Most importantly, the observed suppression in exNMDAR function by both acute and chronic stress implies crucial but overlooked roles of hippocampal exNMDARs in stress-related disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tse, Nath, Larosa and Wong.)

Lay Abstract: In this study, we explored whether pictorial narration could offer a solution to teacher training on effective inclusion of students with autism spectrum disorder in the Lao People's Democratic Republic. For this purpose, pre- and post-training knowledge data were collected from 87 Laotian teachers who participated in teacher training using a pictorial narrative e-module called The Story of Khamdy TM . The teachers' knowledge test results and feedback were analyzed. The findings indicated that teachers' acceptance toward the training method had positive effects on their knowledge changes and supported the use of a pictorial narration approach in imparting knowledge about inclusive education and autism spectrum disorder to teachers in a least developed country.

Purpose: To compare the visual outcomes and complication rates of sutureless cannula-based intraocular lens scleral (SCILS) fixation performed with 25-gauge (25 G) versus 27-gauge (27 G) instrumentation., Methods: A retrospective chart review of consecutive cases of eyes without capsular support that underwent SCILS fixation of a three-piece intraocular lens. Sutureless cannula-based intraocular lens scleral fixation was performed by transconjunctival use of either 25-G or 27-G trocar cannulas. During postoperative follow-up evaluations, visual acuity and intraocular pressure were measured, and slit-lamp and indirect ophthalmoscopy examinations were performed to assess for development of known complications., Results: A total of 69 eyes underwent 25 G (27 eyes) or 27 G (42 eyes) SCILS fixation. The mean preoperative logarithm of the minimum angle of resolution visual acuity trended toward improvement from 0.95 ± 0.68 (20/178 Snellen equivalent) to 0.67 ± 0.64 (20/94 Snellen equivalent) for 25 G group at 1 year. Similar trend toward visual acuity improvement was seen in 27 G group with a mean preoperative logarithm of the minimum angle of resolution visual acuity of 1.43 ± 0.94 (20/538 Snellen equivalent) improving to 0.86 ± 1.00 (20/145 Snellen equivalent) at 1 year. Statistically significant improvement was seen as early as postoperative week one for 27 G group (P < 0.01), whereas statistically significant worsening was noted at the same time in 25 G group (P = 0.01). There was a statistically significant reduction in intraocular lens displacement (P = 0.01) and need for reoperation (P = 0.01) in 27 G group., Conclusion: Compared with 25 G SCILS fixation, eyes managed with 27 G SCILS fixation experienced more rapid visual acuity improvement. In addition, there was a lower rate of complications including intraocular lens displacement and need for reoperation.

Purpose: Advances in radiotherapy have improved tumor control and reduced toxicity in the management of nasopharyngeal carcinoma (NPC). Local failure remains a problem for some patients with advanced primary tumors, and toxicities are significant given the large treatment volume and tumor proximity to critical structures, even with modern photon-based radiotherapy. Proton therapy has unique dosimetric advantages, and recent technological advances now allow delivery of intensity-modulated proton therapy (IMPT), which can potentially improve the therapeutic ratio in NPC. We report our 2-year clinical outcomes with IMPT for NPC., Materials and Methods: We retrospectively reviewed treatment records of patients with NPC treated with IMPT at our center. Demographics, dosimetry, tumor response, local regional control (LRC), distant metastasis, overall survival, and acute and late toxicity outcomes were reviewed. Analyses were performed with descriptive statistics and Kaplan-Meier method. Toxicity was graded per Common Terminology Criteria for Adverse Events (version 4.0)., Results: Twenty-six patients were treated from 2015 to 2020. Median age was 48 years (range, 19-73 years), 62% (n = 16) had T3-T4 disease, 92% (n = 24) were node positive, 92% (n = 24) had stage III-IV disease, and 69% (n = 18) had positive results for Epstein-Barr virus. Dose-painted pencil-beam IMPT was used. Most patients (85%; 22 of 26) were treated with 70 Gy(RBE) in 33 fractions once daily; 4 (15%) underwent hyperfractionated accelerated treatment twice daily. All received concurrent cisplatin chemotherapy; 7 (27%) also received induction chemotherapy. All patients (100%) completed the planned radiotherapy, and no acute or late grade 4 or 5 toxicities were observed. At median follow-up of 25 months (range, 4-60), there were 2 local regional failures (8%) and 3 distant metastases (12%). The Kaplan-Meier 2-year LRC, freedom from distant metastasis, and overall survival were 92%, 87%, and 85% respectively., Conclusion: IMPT is feasible in locally advanced NPC with early outcomes demonstrating excellent LRC and favorable toxicity profile. Our data add to the growing body of evidence supporting the clinical use of IMPT for NPC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Schizophrenia is increasingly being recognized as a disorder of brain circuits of developmental origin. Animal models, however, have been technically limited in exploring the effects of early developmental circuit abnormalities on the maturation of the brain and associated behavioural outputs. This review discusses evidence of the developmental emergence of circuit abnormalities in schizophrenia, followed by a critical assessment on how animal models need to be adapted through optimized tools in order to spatially and temporally manipulate early developmental events, thereby providing insight into the causal contribution of developmental perturbations to schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms. SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders., (Copyright © 2020 the authors.)

A high-rate biological contactor process (HRBC) can be used as primary treatment instead of a clarifier to remove particulate, colloidal and soluble fractions of organic matter via biosorption plus flotation and divert it to anaerobic digestion for methane production, simultaneously reducing secondary aeration energy demand. Pilot and bench tests were conducted at a range of contact times (15-60 min) and contactor dissolved oxygen (DO) (0.2-2.0 mg/L) using waste activated sludge (WAS) from a trickling filter/solids contact (TF/SC) process in the HRBC. Biosorption performance was lowest when contact times were <30 min and unstable at DO < 0.5 mg/L. The overall average of 20% sCOD capture was similar to previous findings by others using WAS from conventional AS. The biomethane potential (BMP) of the HRBC float material can be as high as that of primary sludge (340-400 mL CH 4 /g VS), which is much greater than WAS. Operating the HRBC with a long contact time (>30 min) or with high DO (>1 mg/L) increases the amount of biosorption but reduces the BMP of the float. It was also found that biosorption only effectively occurs when a WAS is paired with the wastewater from the same facility.

Purpose: To determine the efficacy of a novel application of a surgical internal limiting membrane flap technique that requires no additional surgical adjuvants in closure of large full-thickness macular holes (FTMHs)., Methods: The electronic medical records of patients (n = 8) with large (>400 µm) FTMHs repaired with the "Texas Taco" technique were retrospectively reviewed., Results: Operated patients had a mean age of 63.8 ± 19.2 (range, 19-80) years. There were five (62.5%) phakic and three (37.5%) pseudophakic eyes preoperatively. Mean follow-up time was 9.1 ± 4.7 (1.5-14.5) months. Across all patients, mean FTMH diameter at the shortest and greatest widths were 529 ± 101 (404-661) and 1,189 ± 290 (829-1,656) µm, respectively. Mean best-corrected logarithm of the minimum angle of resolution visual acuity was 1.3 ± 0.23 preoperatively (approximately Snellen acuity 20/400) and 0.66 ± 0.40 postoperatively (approximately Snellen acuity 20/100) (P < 0.001). All FTMHs remained closed at all postoperative visits., Conclusion: The Texas Taco technique provided anatomical and functional improvement in challenging cases of large FTMHs without the need of additional surgical adjuvants.

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor. Compared with resilient and nonstressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e., engram cells) in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD and optogenetic approaches to activate and inactivate social defeat-related CA1 engram cells enhanced and suppressed social avoidance, respectively. Increased engram cells in susceptible mice could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-related, but not neutral stimuli-related, CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. The susceptibility to chronic social defeat stress is regulated by hippocampal CA1 engrams for negative memory. Hippocampal negative memory engrams may underlie the vulnerability and expression of cognitive symptoms in depression. SIGNIFICANCE STATEMENT We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams has been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression., (Copyright © 2019 the authors.)

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity. In particular, the rapid insertion of the GluA1 homomeric (GluA1-homo) AMPARs into the postsynaptic membrane is considered to be critical in the expression of hippocampal CA1 long-term potentiation (LTP), which is important for certain forms of learning and memory. However, how the formation and trafficking of GluA1-homo AMPARs are regulated remains poorly understood. Here, we report that p97 specifically interacts with and promotes the formation of GluA1-homo AMPARs. The association with p97 retains GluA1-homo AMPARs in the intracellular compartment under basal conditions, and its dissociation allows GluA1-homo AMPARs to be rapidly inserted into the postsynaptic membrane shortly after LTP induction. Thus, our results shed lights into the molecular mechanisms by which p97 regulates GluA1-homo AMPARs formation and trafficking, thereby playing a critical role in mediating synaptic plasticity.

Background and Objective: Characterize eyes managed with quarterly intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration (nAMD)., Patients and Methods: Treatment-naïve nAMD eyes managed predominately using a treat-and-extend approach that received five or more consecutive quarterly injections from 2005 to 2017., Results: One hundred fifty eyes were retrospectively identified. During quarterly dosing, a mean of 9.8 injections were given over a mean of 29 months. Ninety-one eyes (61%) had no exudative disease recurrence during quarterly dosing. Thirty-three eyes (22%) experienced exudative activity recurrence, with a mean cumulative yearly recurrence rate of 12% and a mean 6-letter loss of visual acuity (VA). Twenty-four eyes (16%) stopped quarterly treatments; nine (38%) of these subsequently experienced exudative activity recurrence with a mean 8-letter VA loss., Conclusion: In this real-world analysis of nAMD managed with quarterly dosing over a mean of more than 2 years' follow-up, 22% experienced disease recurrence during quarterly dosing, and 38% of eyes that stopped quarterly dosing experienced subsequent exudative disease recurrence. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e250-e256.]., (Copyright 2019, SLACK Incorporated.)

In the brain, the TrkA receptor for Nerve Growth Factor (NGF) is expressed primarily in the cholinergic system. TrkA/NGF support neuronal health and function, and deficiencies in this axis are associated with progressive cholinergic neuron atrophy and death, and with cognitive deficit in disorders such as Down's syndrome and Alzheimer's disease. These observations led to the hypothesis that TrkA agonists may rescue atrophic cholinergic neurons and benefit cognition. Indeed, a small molecule TrkA partial agonist called D3 normalized TrkA signals and improved memory in cognitive impairment models of ageing and an APP mouse model of Alzheimer's disease. Paradoxically, in young healthy mice chronic delivery of D3 caused impaired memory without impairing learning, a form of anterograde amnesia. Here, we use this as a model to study the mechanisms of impaired memory. In young healthy mice acute or chronic treatment with D3 induces hyperactivation of TrkA-mediated signals in hippocampus, and causes a deficit in hippocampal-dependent memory consolidation proximal to drug exposure, without affecting learning or memory retrieval. The impairment after acute drug exposure is reversible. The impairment after long-term drug exposure is irreversible, likely due to a decrease in hippocampal CA1 neuron basal arborization. These findings support the notion of a homeostatic role for TrkA in memory, and demonstrate the differential outcomes of TrkA (hyper)activation in healthy versus disease states., Competing Interests: The authors have declared that no competing interests exist.

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

Purpose: This study examines the relationship between dose to corneal substructures and incidence of corneal toxicity within 6 months of proton beam therapy (PBT) for uveal melanoma. We aim to develop clinically meaningful dose constraints that can be used to mitigate corneal toxicity., Methods and Materials: Ninety-two patients were treated with PBT between 2015 and 2017 and evaluated for grade 2+ (GR2+) intervention-requiring corneal toxicity in our prospectively maintained database. Most patients were treated with 50 Gy (relative biological effectiveness [RBE]) in 5 fractions, and all had complete six-month follow-up. Analyses included Mann-Whitney, χ 2 , Fisher exact, and receiver operating curve tests to identify risk factors for GR2+ toxicity. Bivariate logistic regression was used to identify independent dose-volume histogram (DVH) predictors of toxicity after adjustment for the most important clinical risk factor., Results: The 6-month PBT GR2+ corneal toxicity rate was 10.9%, with half of patients experiencing grade 2 toxicity and half experiencing grade 3 toxicity, with no grade 4 events. Patients with anterior chamber tumors had a higher risk (58.3%) for toxicity than those with posterior tumors (0%) or posterior tumors extending past the equator (25%, P < .0001). On univariate analysis, larger size according to Collaborative Ocular Melanoma Studies was associated with increased toxicity rate (P < .004). DVH analysis revealed that cutoffs of 58% for V25, 32% for V45, 51.8 Gy (RBE) for maximum dose, and 32 Gy (RBE) for mean dose to the cornea separated patients into groups experiencing and not experiencing toxicity with 90% sensitivity and ≥96% specificity. Bivariate logistic regression indicated that corneal V25, V45, and mean dose independently predicted for toxicity after adjusting for tumor location., Conclusions: Patients receiving PBT for anterior uveal melanomas experience a high rate of GR2+ corneal toxicity because of increased corneal dose. Anterior location and corneal DVH parameters independently predict toxicity risk. We propose dosimetric constraints to facilitate treatment planning and toxicity mitigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Evaluate the impact of time to surgery and other clinical factors on visual and anatomic outcomes following surgical repair of fovea-sparing rhegmatogenous retinal detachments (RRD)., Methods: Visual and anatomic outcomes were analyzed for their association with clinical factors, including lens status, preoperative visual acuity (VA), contralateral RRD, RRD symptom duration, time to surgery, single-operation anatomic success, number of quadrants involved, posterior RRD extent, RRD extent closest to the fovea, number of retinal breaks, quadrants with retinal breaks, and surgery performed Saturday or Sunday versus Monday-Friday., Results: Medical records of 423 eyes with fovea-sparing RRD repaired with pneumatic retinopexy (PR), scleral buckle (SB), pars plana vitrectomy (PPV), and PPV with SB (PPV/SB) were included. Sixty-seven percent and 89% were operated within 24 and 72 h of RRD presentation, respectively. Single-operation anatomic success rates were 59%, 89%, 84%, and 92% for PR, SB, PPV, and PPV/SB interventions, respectively. Final anatomic success was 100%. Three clinical factors correlated with faster time to surgery: shorter symptom duration (p < 0.02), RRD superior location (p = 0.001), and posterior extension into the macula (p = 0.01). The time to surgery did not correlate with visual or anatomic outcomes. Two clinical factors positively correlated with postoperative vision: preoperative VA (r > 0.25, p < 0.04) and single-operation anatomic success (p < 0.04). Surgeries performed on Monday through Friday (n = 411) were associated with better anatomic outcomes compared with the limited number performed on Saturday or Sunday (n = 12) (p = 0.005), although a greater proportion of operated cases over the weekend were PR., Conclusions: In the context of the current series, time to surgery did not correlate with visual or anatomic outcomes following the surgical repair of fovea-sparing RRDs. Preoperative VA and single-operation anatomic success correlated with improved visual outcome.

Sporadic Alzheimer's disease (AD) is the most common cause of dementia. However, representative experimental models of AD have remained difficult to produce because of the disease's uncertain origin. The Polycomb group protein BMI1 regulates chromatin compaction and gene silencing. BMI1 expression is abundant in adult brain neurons but down-regulated in AD brains. We show here that mice lacking one allele of Bmi1 (Bmi1+/-) develop normally but present with age cognitive deficits and neurodegeneration sharing similarities with AD. Bmi1+/- mice also transgenic for the amyloid beta precursor protein died prematurely and present aggravated disease. Loss of heterochromatin and DNA damage response (DDR) at repetitive DNA sequences were predominant in Bmi1+/- mouse neurons and inhibition of the DDR mitigated the amyloid and Tau phenotype. Heterochromatin anomalies and DDR at repetitive DNA sequences were also found in AD brains. Aging Bmi1+/- mice may thus represent an interesting model to identify and study novel pathogenic mechanisms related to AD.

There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence., (Copyright © 2018. Published by Elsevier B.V.)

Background: Pancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy., Purpose: Our previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied., Methods: The anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting., Results: The combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination., Conclusion: Gem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Maternal care shapes individual differences in fear-associated neural circuitry. In rats, maternal licking and grooming (LG) in early life regulates ventral hippocampal (VH) function and plasticity in adulthood, but its consequent effect on the regulation of fear memories remains unknown. We report an effect of maternal care on generalization of learned fear, such that offspring of high LG mothers express generalized fear responses when confronted with neutral stimuli following auditory fear conditioning. These animals simultaneously display a reduction in the magnitude of VH long-term potentiation (LTP) expressed and reduced input-output transformation in Schaffer collateral synapses. Inhibition of VH-LTP during learning specifically increases fear generalization in offspring of low LG mothers during recall, suggesting a role for VH synaptic plasticity in the specification of fear memories. These findings suggest that rearing by low LG dams enhances the efficacy of fear-related neural systems to support accurate encoding of fear memories through effects on the VH.

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted 2-4 . The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation 5-7 , but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

Purpose: To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME)., Design: Phase I/II prospective, randomized, controlled clinical trial., Participants: Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus., Methods: Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1-disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated., Main Outcome Measures: Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered., Results: At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters (P = 0.20) and mean CRT improved 302 and 152 μm (P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10-34) and 27.1 (range, 12-36), with 73% (362/496) and 80% (433/538) of PRN injections administered (P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively (P = 0.30)., Conclusions: In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Suboptimal maternal care is a form of chronic early-life stress (ELS) and a risk factor for mental illness and behavioral impairments throughout the life span. The amygdala, particularly the basolateral amygdala (BLA), exhibits exquisite sensitivity to ELS and could promote dysregulation of stress reactivity and anxiety-related disorders. While ELS has profound impacts on the adult or adolescent amygdala, less is known regarding the sensitivity of the preweaning BLA to ELS. We employed a naturalistic rodent model of chronic ELS that limits the amount of bedding/nesting material (LB) available to the mother between postnatal day (PND) 1-9 and examined the morphological and functional effects in the preweaning BLA on PND10 and 18-22. BLA neurons displayed dendritic hypertrophy and increased spine numbers in male, but not female, LB pups already by PND10 and BLA volume tended to increase after LB exposure in preweaning rats, suggesting an accelerated and long-lasting recruitment of the amygdala. Morphological changes seen in male LB pups were paralleled with increased evoked synaptic responses recorded from BLA neurons in vitro, suggesting enhanced excitatory inputs to these neurons. Interestingly, morphological and functional changes in the preweaning BLA were not associated with basal hypercorticosteronemia or enhanced stress responsiveness in LB pups, perhaps due to a differential sensitivity of the neuroendocrine stress axis to the effects of LB exposure. Early changes in the synaptic organization and excitability of the neonatal amygdala might contribute to the increased anxiety-like and fear behavior observed in adulthood, specifically in male offspring., (Copyright © 2017 Elsevier Inc. All rights reserved.)