Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress.

BACKGROUND: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. METHODS: We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. RESULTS: The expression of δ subunit-containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. CONCLUSIONS: Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Parental Relationship Quality and Adolescent Depressive Symptoms: Investigating The Role of Parental Warmth and Hostility in United States Military Families.

Military life is characterized by regular transitions; thus, parents are positioned to serve as stable protective factors for adolescents. We investigated a theory-informed model that assessed direct and indirect relationships between parental relationship quality, parental behaviors, and adolescent depressive symptomatology using cross-sectional data of military families in the United States (US). Participant families (N = 229), recruited via convenience sampling to take a computer-based survey, included an active duty father, his spouse, and an adolescent. Mother's couple relationship quality was indirectly linked to adolescent depressive symptoms through maternal warmth. Conversely, father's couple relationship quality was indirectly linked to adolescent depressive symptoms via paternal hostility. In other words, parental couple relationship quality was indirectly related to adolescent depressive symptoms, but this relationship differed by parent (i.e., warmth for mothers and hostility for fathers). Findings were similar for adolescent boys and girls.

A Screen for Synaptic Growth Mutants Reveals Mechanisms That Stabilize Synaptic Strength.

Synapses grow, prune, and remodel throughout development, experience, and disease. This structural plasticity can destabilize information transfer in the nervous system. However, neural activity remains stable throughout life, implying that adaptive countermeasures exist that maintain neurotransmission within proper physiological ranges. Aberrant synaptic structure and function have been associated with a variety of neural diseases, including Fragile X syndrome, autism, and intellectual disability. We have screened 300 mutants in Drosophila larvae of both sexes for defects in synaptic growth at the neuromuscular junction, identifying 12 mutants with severe reductions or enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed that synaptic strength was unchanged in all but one of these mutants compared with WT. We used a combination of genetic, anatomical, and electrophysiological analyses to illuminate three mechanisms that stabilize synaptic strength despite major disparities in synaptic growth. These include compensatory changes in (1) postsynaptic neurotransmitter receptor abundance, (2) presynaptic morphology, and (3) active zone structure. Together, this characterization identifies new mutants with defects in synaptic growth and the adaptive strategies used by synapses to homeostatically stabilize neurotransmission in response.SIGNIFICANCE STATEMENT This study reveals compensatory mechanisms used by synapses to ensure stable functionality during severe alterations in synaptic growth using the neuromuscular junction of Drosophila melanogaster as a model system. Through a forward genetic screen, we identify mutants that exhibit dramatic undergrown or overgrown synapses yet express stable levels of synaptic strength, with three specific compensatory mechanisms discovered. Thus, this study reveals novel insights into the adaptive strategies that constrain neurotransmission within narrow physiological ranges while allowing considerable flexibility in overall synapse number. More broadly, these findings provide insights into how stable synaptic function may be maintained in the nervous system during periods of intensive synaptic growth, pruning, and remodeling.

Placental Location and the Development of Hypertensive Disorders of Pregnancy.

OBJECTIVES: Abnormal placentation is an important factor in the pathogenesis of preeclampsia. As a result of diminished blood flow, the incidence of preeclampsia might be higher in patients with laterally located placentas compared to patients with centrally located placentas. The objective of this study was to evaluate the relationship between placental location and the development of hypertensive disorders of pregnancy. METHODS: Patients with singleton pregnancies who were seen in our ultrasound unit and delivered at our institution from October 2014 to April 2015 were included. The incidence of hypertensive disorders was compared in those with a lateral placental location and those with centrally located placentas (placental locations other than lateral). Baseline characteristics and pregnancy outcomes were compared between groups. The χ2 test, Fisher exact test, Mann-Whitney U test, and t test were used when appropriate. P < .05 was considered significant. RESULTS: We included 464 patients; 411 (88.57%) had centrally located placentas, and 53 (11.42%) had laterally located placentas. The incidence of hypertensive disorders of pregnancy was similar between groups (21% versus 19%; P = .71). Gestational age at delivery (P = .73), and small for gestational age (P = .96) were also similar between our study groups. CONCLUSIONS: In our study, there was no difference in the rate of hypertensive disorders of pregnancy between patients with central and laterally located placentas.

T1 difficulty affects the AB: manipulating T1 word frequency and T1 orthographic neighbor frequency.

Colored target words were presented with distractor nonwords in a rapid serial visual presentation (RSVP) task. In Experiment 1, the attentional blink (AB) effect on T2 accuracy was larger when T1 was a difficult (low-frequency) word than when it was a high-frequency word. In Experiment 2 the effect of T1 frequency on the AB was replicated in a between-participants design, and the frequency of T1's one-letter different neighbors (e.g., case, bare, for care) interacted with T1 frequency in its effects on T2 accuracy. Experiment 3 confirmed the effect of T1 frequency over 6 T1-T2 lags. The effects of T1 characteristics were sensitively assessed in the AB and were more consistent with resource depletion theories than control-process accounts.

Evidence from the attentional blink for different sources of word repetition effects.

T2 in an attentional blink paradigm served as a high- or low-frequency prime word for a subsequent repeated target. Consistent with research in visual word identification, only reported primes facilitated the identification of a target repeated approximately 8s after RSVP. Priming was greater for low- than high-frequency words. Analogous with masked priming, a blinked T2 facilitated report of a repeated target occurring 318ms after T2 in RSVP. The blinked repetition priming effect was additive with target frequency. These results indicate that: (1) the outcomes of processing prime words are a key factor in repetition priming effects, with blinked and reported T2s behaving like masked and unmasked primes, respectively, (2) there may be different sources of repetition effects, (3) there is a consistent cross-paradigm pattern of repetition effects that occurs as a function of prime-target interval and the ability to identify the word on its first and second presentation.