Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

Memory formation, reconsolidation, extinction and forgetting in lymnaea stagnalis

Bibliography: p. 203-227Some pages are in colour

Not Just How Much, But How Many: Overall and Domain-Specific Activity Variety and Cognitive Functioning in Adulthood.

OBJECTIVES: Active lifestyles are related to higher levels of cognitive functioning. Fewer studies have examined the importance of engaging in different activities (activity variety) for cognitive functioning. Moreover, it is unclear whether activity variety in specific domains (i.e., cognitive, physical, or social) is important for cognitive health. The current study examined whether overall activity variety as well as variety in specific domains relate to cognitive functioning. METHODS: In Waves 2 and 3 of the Survey of Midlife Development in the United States, 3,337 adults reported their activity engagement and completed a cognitive battery. For longitudinal analyses, 2,049 participants were classified into 4 groups based on their rank ordering of activity variety across 9 years (remained high, increased, decreased, or remained low). RESULTS: Cross-sectional analyses revealed that overall activity variety was related to higher cognitive functioning over and above activity frequency; physical and social activity variety each contributed significantly and uniquely to this association. Longitudinal analyses revealed that those with consistently low overall activity variety at both waves had lower cognitive functioning at Wave 3 than those with high activity variety at either wave, after adjusting for cognitive functioning at Wave 2. Those with consistently high or increasing social activity variety had higher cognitive functioning at Wave 3 than participants with low activity variety at both waves. DISCUSSION: Findings suggest that activity variety, particularly in the social domain, is related to concurrent and future cognitive function across adulthood

Psychological and physiological correlates of stimulus discrimination in adults

The discrimination of cues in the environment that signal danger ("fear cue") is important for survival but depends critically on the discernment of such cues from ones that pose no threat ("safety cues"). In rodents, we previously demonstrated the underlying neurobiological mechanisms that support fear versus safety discrimination and documented that these mechanisms extend to the discrimination of reward as well. While learning about reward is equally important for survival, it remains an under-studied area of research, particularly in human studies of conditional discrimination. In the present study, we translated our rodent task of fear reward and neutral discrimination (fear, reward, and neutral discrimination [FRND]) for use in humans. Undergraduate students (N = 53) completed the FRND while electrodermal activity was recorded. Skin conductance response (SCR) amplitude, a marker of arousal response, was derived for fear, reward, and neutral cues that signaled no outcome; critical trials assessed conditional discrimination using combined fear + neutral and reward + neutral cues. Participants provided likeability ratings for each cue type. Results demonstrated that participants rated reward cues the best, fear cues the worst, and neutral cues in between, while SCR amplitude was largest for fear and reward cues and lowest for neutral cues. SCR amplitudes were reduced for fear + neutral (compared to fear) and reward + neutral cues (compared to reward). Results demonstrate that the FRND is a useful paradigm for the assessment of psychological and physiological discrimination of fear and reward. Implications and directions for future work are discussed

Improving MICU O:E mortality ratio

"Improve physician and nursing documentation to capture severity of illness, comorbidity, and risk of mortality for Medicare payer patients with diagnosis of sepsis, respiratory failure, and poisoning in patients: greater than 18 years of age; greater than or equal to 1 day of ICU care, and are discharged from either Pulmonary/Critical Care, Internal Medicine, or Family Medicine. As measured by: 10 percent improvement in observed to expected mortality ratio, comorbidity and major comorbidity (CC/MCC) capture rates through chart review of all patients and education of clinicians, and increase reimbursement through increase capture of MCCs and CCs."--Aim statement