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Motivated behaviors are often studied in isolation to assess labeled lines of neural connections underlying innate actions. However, in nature, multiple systems compete for expression of goal-directed behaviors via complex neural networks. Here, we examined flexible survival decisions in animals tasked with food seeking under predation threat. We found that predator exposure rapidly induced physiological, neuronal, and behavioral adaptations in mice highlighted by reduced food seeking and consumption contingent on current threat level. Diminishing conflict via internal state or external environment perturbations shifted feeding strategies. Predator introduction and/or selective manipulation of danger-responsive cholecystokinin (Cck) cells of the dorsal premammilary nucleus (PMd) suppressed hunger-sensitive Agouti-related peptide (AgRP) neurons, providing a mechanism for threat-evoked hypophagia. Increased caloric need enhanced food seeking under duress through AgRP pathways to the bed nucleus of the stria terminalis (BNST) and/or lateral hypothalamus (LH). Our results suggest oscillating interactions between systems underlying self-preservation and food seeking to promote optimal behavior., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

In humans, traumatic social experiences can contribute to psychiatric disorders 1 . It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance 2,3 . In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward 4,5 . Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca 2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NT LS ) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NT LS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NT LS neurons that occlude social reward processing., (© 2022. The Author(s).)

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1β (IL-1β) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1β in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1β signaling in the DRN controls expression of aggressive behavior., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, although gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice., Competing Interests: KL, KC, MK, LP, CB, SR No competing interests declared, (© 2021, LeClair et al.)

The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper ® home-cages and the video-based tracking software, EthoVision ® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a "home-cage", we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios., Competing Interests: BB and QP were employed by F. Hoffman-La Roche Ltd. BK and ML are employed by Synaptologics BV. ED, FG, LN, RFR, and RT are employed by Noldus Information Technology BV. AS participates in a holding that owns shares of Synaptologics BV. The remaining 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 Grieco, Bernstein, Biemans, Bikovski, Burnett, Cushman, van Dam, Fry, Richmond-Hacham, Homberg, Kas, Kessels, Koopmans, Krashes, Krishnan, Logan, Loos, McCann, Parduzi, Pick, Prevot, Riedel, Robinson, Sadighi, Smit, Sonntag, Roelofs, Tegelenbosch and Noldus.)

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

When presented with a choice, organisms need to assimilate internal information with external stimuli and past experiences to rapidly and flexibly optimize decisions on a moment-to-moment basis. We hypothesized that increasing hunger intensity would curb expression of social behaviors such as mating or territorial aggression; we further hypothesized social interactions, reciprocally, would influence food consumption. We assessed competition between these motivations from both perspectives of mice within a resident-intruder paradigm. We found that as hunger state escalated, resident animal social interactions with either a female or male intruder decreased. Furthermore, intense hunger states, especially those evoked via AgRP photoactivation, fundamentally altered sequences of behavioral choice; effects dependent on food availibility. Additionally, female, but not male, intrusion attenuated resident mouse feeding. Lastly, we noted environmental context-dependent gating of food intake in intruding mice, suggesting a dynamic influence of context cues on the expression of feeding behaviors., Competing Interests: CB, SF, JN, AS, JL, TD, MK No competing interests declared

Behavioral choice is ubiquitous in the animal kingdom and is central to goal-oriented behavior. Hypothalamic Agouti-related peptide (AgRP) neurons are critical regulators of appetite. Hungry animals, bombarded by multiple sensory stimuli, are known to modify their behavior during times of caloric need, rapidly adapting to a consistently changing environment. Utilizing ARC AgRP neurons as an entry point, we analyzed the hierarchical position of hunger related to rival drive states. Employing a battery of behavioral assays, we found that hunger significantly increases its capacity to suppress competing motivational systems, such as thirst, anxiety-related behavior, innate fear, and social interactions, often only when food is accessible. Furthermore, real-time monitoring of ARC AgRP activity revealed time-locked responses to conspecific investigation in addition to food presentation, further establishing that, even at the level of ARC AgRP neurons, choices are remarkably flexible computations, integrating internal state, external factors, and anticipated yield. VIDEO ABSTRACT., (Published by Elsevier Inc.)

Background: To assess baseline knowledge and awareness of cardiometabolic comorbidities in subjects with psoriasis. To determine the impact of a verbal scripted educational intervention., Methods: Fifty-six adults with a clinical diagnosis of moderate to severe psoriasis completed a 12-item questionnaire about psoriasis comorbidity awareness and knowledge at 2 time points: pre-intervention (PR-I) and post-intervention (PO-I). The PR-I questionnaire collected information on history of psoriasis and cardiometabolic disease. A 5-minute scripted educational intervention was administered during a single study visit to subjects immediately after PR-I but prior to PO-I questionnaires. Subjects also completed a final questionnaire at 2 months follow-up (2-MF). Responses were statistically analyzed using McNemar's test., Results: Fifty-six subjects (26 females, 30 males, mean age 51 years, range 21 to 83 years) participated in the PR-I and PO-I and 46 (82%) participated in 2-MF. Significant improvements were noted for 10 of 11 questions between PR-I and PO-I, and 8 of the scores remained significantly improved (compared with baseline) at 2-MF (P<0.05). At 2-MF, 65% of subjects had seen a primary care physician within the 2-month interval from PO-I to 2-MF, and another 26% planned to visit a primary care physician in the near future. Furthermore, 85% had checked their blood pressure in the past 2 months., Conclusions: Measures of knowledge and awareness of psoriasis and cardiometabolic comorbidities were significantly improved at PO-I and retained for most measures at 2-MF. An educational intervention, as utilized in this study, warrants consideration to enhance cardiometabolic-based knowledge and awareness in patients with psoriasis. , , J Drugs Dermatol. 2016;15(10):1176-1180.

Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics. In this review we will provide a brief overview of DREADDs, their implementation, and the advantages and disadvantages of their use in animal systems. We also will provide numerous examples of their use across a broad variety of biomedical research fields., (Copyright © 2016 the authors 0270-6474/16/369268-15$15.00/0.)

Hypothalamic AgRP neurons potently coordinate feeding behavior to ensure an organism's viability. However, their acute role in glucose-regulatory function remains to be addressed. Steculorum et al. now report that activation of a specific set of AgRP neurons results in an impairment of insulin-stimulated glucose uptake in brown fat through a myogenic signature program., (Published by Elsevier Ltd.)

The objective of this study was to determine if the addition of 1% tetracaine to 0.25% bupivacaine prolonged the duration of postoperative analgesia of supraclavicular brachial plexus nerve blockade for patients undergoing ambulatory shoulder surgery. We conducted a prospective, double-blinded, randomized controlled clinical study at an ambulatory surgery center utilizing ultrasound- and nerve stimulation-guided supraclavicular nerve blockade for postoperative analgesia. The control group received 30 mL of 0.25% bupivacaine plus 4 mL preservative-free saline. The study group received 30 mL of 0.25% bupivacaine plus 4 mL of 1% tetracaine. Patients documented their visual analog scale scores and intake of pain medications for 3 days. Primary outcomes included time of first postoperative pain, time of first postoperative pain pill, and time of return of motor and sensory function. Secondary outcomes included pain score and pain medication intake trends and adverse events secondary to the nerve block. A total of 84 patients completed the study, 42 patients in each group. The study group was statistically significantly older than the control group (mean age, 54 vs 48 years; P = 0.04). The mean duration of analgesia was 16.6 ± 8.3 h for the control group and 17.1 ± 7.3 h for the study group (P = 0.69). No outcomes were statistically different. In conclusion, there was no significant difference in duration of postoperative analgesia with the addition of 1% tetracaine to 0.25% bupivacaine in supraclavicular brachial plexus nerve blockade. No differences were identified in postoperative pain medications, pain scores, or complications.

Background: In this pilot study, we attempted to validate three-dimensional transesophageal echocardiography (3DTEE) cardiac output and assess its feasibility intraoperatively., Methods: Twenty patients undergoing cardiac surgery underwent simultaneous cardiac output determinations during the clinically stable prebypass period by 3DTEE and thermodilution., Results: The correlation coefficient between cardiac output measured by the two methods was 0.86. The 3DTEE mean bias was 0.27 L/min, limits of agreement -1.64 to 2.17 L/min (approximately +/-35%). Three-dimensional data acquisition averaged 43 s; postprocessing took 7 min., Conclusions: Three-dimensional TEE can measure cardiac output and is feasible perioperatively. Measurements have good correlation with thermodilution, though with a significant bias and wide limits of agreement.

The oral administration of 1-alpha-acetylmethadol (LAAM) in the mouse was shown to cause a significant elevation in the hepatic LAAM N-demethylase activity. Compared to the self-induction phenomena found with methadone and propoxyphene, LAAM was three and two times more potent, respectively, on a molar basis than these two structurally similar narcotic analogs. Moreover, microsomal induction by LAAM resulted in significant elevations of aminopyrine N-demethylase and aniline hydroxylase activities. These effects were also correlated with a dose related decrement of pentobarbital sleeping time. Thus LAAM appears to be a relatively potent inducer of microsomal metabolism.