Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. Although the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal underpinnings of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear- and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreERT2 mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these socially active neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neural ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

The serotonin 1A receptor (5-HT1A) system has been extensively implicated in modulating mood and behavior. Notably, 5-HT1A levels in humans display remarkable variation, and differences in receptor levels have been linked with a variety of psychiatric disorders. Further, reduction of receptor levels by 30-50% in mice suggests that changes in receptor levels that model existing human variation are sufficient to drive behavioral alterations. As a result, genetic mechanisms that modulate human 5-HT1A levels may be important for explaining individual differences in mood and behavior, representing a potential source of psychiatric disease risk. One common genetic variant implicated in differential 5-HT1A levels is the G/C single nucleotide polymorphism (SNP) rs6295, located upstream of the human 5-HT1A gene. This SNP differentially binds the transcription factor, NUDR/Deaf1, leading to cell-type specific effects on transcription in vitro. To investigate the direct effects of this SNP in the heterogeneous cellular context of the brain, we generated humanized transgenic mice using a design that maximized the local transcriptional landscape of the human HTR1A gene while also controlling for effects of genomic insertion location. We integrated a 180 kb human bacteria artificial chromosome (BAC) transgene containing G- and C-alleles of rs6295 flanked by FRT or loxP sites. Subsequent deletion of each allele by Cre- or Flp-recombinase resulted in rs6295G and C alleles in the same genomic location. These alleles were bred onto a 5-HT1A null mouse such that the human BAC was the sole source of 5-HT1A in these mice. We generated three separate lines, two of which had detectable human 5-HT1A levels in the brain, although none displayed expression in the raphe. Of these, one line exhibited rs6295-dependent differences in 5-HT1A levels and differences in behavior, even though the overall levels were considerably lower than native expression levels. The line-dependent effect of rs6295 on protein levels and behavior may depend upon differences in background genetic factors or different insertion sites across each line. This work confirms that relatively subtle differences in 5-HT1A levels can contribute to differences in behavior and highlights the challenges of modeling human noncoding genetic variation in mice.

Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. While the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal bases of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially-active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreERT2 mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these socially-active neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neuronal ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

BACKGROUND/AIMS:No single classification system has so far effectively predicted the severity for Acute Pancreatitis (AP). This study compares the effectiveness of classification systems: Original Atlanta (OAC), Revised Atlanta (RAC), Determinant based classification (DBC), PANC 3, Harmless AP Score (HAPS), Japanese Severity Score (JSS), Symptoms Nutrition Necrosis Antibiotics and Pain (SNNAP), and Beside Index of Severity for AP (BISAP) in predicting outcomes in AP.METHODS:Scores for BISAP, Panc 3, HAPS, SNNAP, OAC, RAC, and DBC were calculated for 221 adult patients hospitalized for AP. Receiver Operating Characteristic curve analysis and Akaike Information Criteria were used to compare the effectiveness of predicting need for surgery, intensive care unit (ICU) admission, readmission within 30 days, and length of hospital stay.RESULTS:Both the RAC and the DBC strongly predict the length of hospital stay (p < 0.0001 for both) and ICU admission (p < 0.0001 for both). Additionally, both BISAP and PANC 3 showed weak predictive capacity at identifying length of stay and ICU admission.CONCLUSIONS:We suggest that BISAP and PANC3 be obtained within the initial 24 h of hospitalization to offer an early prediction of length of stay and ICU admission. Subsequently, RAC and DBC can offer further information later in the course of the disease.

Introduction: Acute pancreatitis (AP) is a common gastrointestinal disorder associated with a high morbidity and mortality rate. Current guidelines advocate the need for aggressive fluid resuscitations within the initial 24 hours to prevent patient deterioration. This study aims to explore whether fluid volume by 12 hours post presentation is associated with poorer outcomes. Methods: This retrospective cohort study was conducted at Long Island Jewish Medical Center (LIJ) and North Shore University Hospital (NSUH) between April and September 2015. 214 non-transferred, adult patients without organ failure were identified using the ICD-9 discharge code for AP (577.0). All patients met the criteria for AP on having two out of three criteria: (1) lipase or amylase >3 times the upper limit of normal, (2) radiological findings of AP, (3) presence of epigastric pain. IV fluid volume at 12 hours was treated as a continuous variable. A univariate followed by a multivariate analysis was conducted to determine if there was an association between increasing fluid volumes and various outcome variables. Results: Multivariate analysis revealed that fluid volume was independently associated with the development of necrosis (P<0.01), length of stay (P=0.03) and the development of pleural effusion (P=0.01). Specifically, a 100 mL increase in volume was associated with a 10% increase in the odds developing necrosis and a 6% increase in the odds of developing pleural effusion. The multivariate analysis also revealed that hypertension was strongly associated with the risk of developing organ failure (P<0.001). Conclusion: These results further support the hypothesis that necrosis is an early phenomenon, and aggressive fluid resuscitation may not suppress it. The risk of pleural effusion development was higher with increasing fluid volumes. Current guidelines on fluid therapy in AP may not be appropriate for every patient.

Introduction: Nutritional support is associated with better patient outcomes in acute pancreatitis (AP). However current tools to assess nutritial status including NSR-2002, SNAQ, BMI, and weight have inherent limitations in certain populations and their interpretation can be subjective. Previous literature has demonstrated that the L3 skeletal muscle index (L3-SMI) provides a more accurate, faster, and objective way to assess nutritional status. This study explored the relationship between diminished nutritional status using L3-SMI and the severity and outcomes of acute pancreatitis. Methods: This retrospective cohort study was conducted at Long Island Jewish Medical Center (LIJ) and North Shore University Hospital (NSUH). Patients met the criteria for AP on having two out of three criteria: (1) lipase or amylase > 3 times the upper limit of normal, (2) radiological findings of AP, (3) presence of epigastric pain. The L3 skeletal muscle index was obtained for 166 patients with AP by normalizing the calculated L3 skeletal muscle area with the patient height. These values divided patients into undernourished and adequately nourished groups based on sex-specific cutoffs. The indices along with the clinical data were used to determine the correlation between nutritional status and outcomes including length of hospital stay, admission to the ICU, incidence of organ failure, and BISAP classification. Results: Results showed that undernourished patients are more likely to be associated with worse outcomes and more severe AP. However, results were not statistically significant. Organ failure appeared to be the most closely associated with nutritional status (p = .0513). Further, hypertension was shown to be a confounding variable between nutritional status and organ failure. Conclusion: The relationship between nutritional status and outcomes as well as severity of acute pancreatitis is not statistically significant, however it is possible that the study population size was not adequate to power this study, and further studies should be done to explore this relationship.

This chapter focuses on the RFDAC (also termed as DPA) for the polar transmitter. The RFDAC also serves as a mixer combining amplitude and phase modulation. A digital clock, running at RF carrier with phase modulation, contains the phase information generated by the DCO. The RFDAC achieves its amplitude modulation by using a combination of integer and fractional transistors. The transistors are switched at a rate represented by the DCO clock. Fractional resolution is achieved using second-order Sigma-Delta modulator. Dynamic Element Matching (DEM) is used to randomize the mismatches between integer transistors. Any systematic mismatch between integer and fractional transistors is corrected by using predistortion. Digital invertor-based delay alignment is used to ensure correct timing of the DAC element switching with reference to DCO clock with on-chip self-calibration to find optimum code for the delay alignment. Analysis of on-chip clock feed-thru is presented along with idle-tone-based method to characterize the magnitude and phase of the coupling path.

The social modulation of fear and anxiety represents a highly conserved trait. Humans and rodents display decreases in fear, anxiety, and stress responses when a conspecific is present. The neural basis of this is not well understood.

The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health.

The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.