Genetic loss of the dopamine transporter significantly impacts behavioral and molecular responses to sub-chronic stress in mice.

Dopaminergic neurotransmission has emerged as a critical determinant of stress susceptibility and resilience. Although the dopamine transporter (DAT) is known to play a key role in maintaining dopamine (DA) homeostasis, its importance for the regulation of stress susceptibility remains largely unknown. Indeed, while numerous studies have examined the neurochemical and behavioral consequences of genetic loss of DAT, very few have compared responses to stress in wild-type and DAT-knockout (KO) animals. The current study compared the responses of male and female WT and DAT-KO mice to a model of sub-chronic stress. Our results reveal that DAT-KO mice are resistant to stress-induced increases in the latency to enter the light chamber of the light-dark emergence test and demonstrate that DAT-KO mice exhibit baseline reductions in forced swim test immobility and grooming time in the splash test of grooming behavior. In addition to these behavioral changes, our results highlight the importance of sex and dopaminergic neurotransmission on stress-induced changes in the expression and phosphorylation of several signal transduction molecules in the nucleus accumbens that have previously been implicated in the regulation of stress susceptibility, including ERK, GSK3ß, and ΔFosB. Overall, these results provide further evidence of the importance of dopaminergic neurotransmission in regulating stress susceptibility and suggest that genetic loss of DAT prevents stress-induced increases in anxiety-like behavior.

Estrogen administration and withdrawal in a model of hormone-simulated pregnancy lead to alterations in behavior and gene expression but do not induce depression-like phenotypes in mice.

Pregnancy and the post-partum period are associated with substantial fluctuations in hormone levels and are frequently associated with significant stress. Many individuals also experience affective disturbances during the peri­partum period, including anxiety, the 'baby blues,' and post-partum depression. However, the extent to which these affective changes result from rapidly altering hormone levels, increased stress, or the combination of both remains largely unknown. The current study sought to evaluate the consequences of pregnancy-like hormonal changes on behavior and gene expression in c57BL/6 mice in the absence of stress using a hormone-simulated pregnancy model. Our results reveal that animals receiving hormone injections to simulate the high levels of estrogen observed in late pregnancy and animals withdrawn from estrogen to mimic the rapid decline in this hormone following parturition both exhibit increased anxiety-like behavior compared to ovariectomized controls in the novel open field test. However, no other significant anxiety- or depression-like alterations were observed in either hormone-treated group compared to ovariectomized controls. Both hormone administration and estrogen withdrawal were shown to induce several significant alterations in gene expression in the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. In contrast to the estrogen withdrawal hypothesis of post-partum depression, our results suggest that this method estrogen withdrawal following hormone-simulated pregnancy in the absence of stress does not induce phenotypes consistent with post-partum depression in c57BL/6 mice. However, given that estrogen withdrawal does lead to significant gene expression changes in two stress-sensitive brain regions, it remains possible that estrogen withdrawal could still contribute to affective dysregulation in the peri-partum period by influencing susceptibility to stress. Future research is required to evaluate this possibility.

Chronic, but not sub-chronic, stress increases binge-like alcohol consumption in male and female c57BL6 mice.

Stress is known to contribute to mental illness and alcohol use disorders, which are highly prevalent and lead to considerable disability. These stress-related disorders are characterized by significant sex differences, which remain poorly understood. Preclinical research comparing the effects of stress in males and females has the potential to provide new insights into the neurobiology of these conditions. The current study compared the effects of chronic and sub-chronic exposure to variable environmental stressors on binge-like alcohol consumption using the drinking-in-the-dark model in male and female c57BL6 mice. The results reveal that chronic, but not sub-chronic, exposure to variable stress increases alcohol intake in both sexes. Stress-induced alterations in gene expression were also compared in the nucleus accumbens, a brain region widely known to play a key role in stress susceptibility and reward processing. Real-time PCR data indicate that chronic, but not sub-chronic, environmental stress leads to downregulation of adenosine 2A (A2A) receptor mRNA. By contrast, sub-chronic stress increased CREB expression, while chronic stress did not. Several sex differences in the effects of stress on gene expression were also noted. Our results demonstrate that reductions in A2A receptor mRNA in the nucleus accumbens are associated with the increased binge drinking of chronically stressed animals, but future work will be required to determine the functional importance of this gene expression change. Continuing to define the molecular alterations associated with stress-induced increases in alcohol intake has the potential to provide insights into the development and progression of stress-related disorders.

Early life maternal separation induces sex-specific antidepressant-like responses but has minimal effects on adult stress susceptibility in mice.

Early life stress is known to increase the risk of depression and anxiety disorders, which are highly prevalent conditions that disproportionately affect women. However, the results of preclinical studies have been mixed, with some work suggesting that early life stress promotes anxiety-like behavior and/or increases susceptibility to subsequent stressors, and other research suggesting that early life stress reduces anxiety-like behavior and/or confers resilience to subsequent stress exposure. It is likely that factors such as sex and the timing and severity of early life and adult stress exposure dictate whether a particular early life experience promotes adaptive vs. maladaptive behavior later in life. Most work in this area has focused exclusively on males, but several sex differences in the effects of early life stress on subsequent stress susceptibility have been reported. The current study examined the impact of early life maternal separation on susceptibility to behavioral alterations induced by 3 days of variable stress in adulthood in male and female c57BL6 mice. Our results indicate that 3 days of adult stress is sufficient to increase anxiety-like behavior in several paradigms and to increase immobility in the forced swim test. In contrast, a history of maternal separation reduces anxiety-like behavior in several tests, particularly in males. These findings could contribute to our understanding of sex differences in mental illness by demonstrating that males are more likely than females to display adaptive responses to mild early life stressors.

Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice.

RATIONALE: Although pharmacotherapies are often effective in reducing binge eating in conditions such as bulimia nervosa and binge eating disorder, subsets of patients do not benefit sufficiently from existing treatments, and the reasons for treatment failure remain unclear. OBJECTIVES: This study aimed to evaluate whether genetic reductions in brain serotonin influence binge eating and/or the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce binge eating in mice. METHODS: This study used a validated model of binge-like consumption of high-fat diet to compare binge-like food intake in control and fluoxetine-treated wild-type and serotonin-deficient mice from the tryptophan hydroxylase 2 (R439H) knock-in line. In addition, real-time PCR was used to evaluate potential genotype and sex differences in the effects of fluoxetine on gene expression in the raphe nucleus. RESULTS: The results reveal that brain serotonin deficiency is sufficient to increase binge eating in males, but not females. However, while chronic fluoxetine reduced binge eating in both genotypes of males and in wild-type females, it failed to reduce binge eating in serotonin-deficient females. Transcriptional responses to chronic fluoxetine were also characterized by sex and genotype differences. CONCLUSIONS: Overall, this study revealed significant sex differences in the effects of fluoxetine and brain serotonin deficiency on binge-like food intake and suggests that low brain serotonin could impact eating disorders both by promoting binge eating and by limiting the efficacy of fluoxetine to reduce binge eating.

Sub-chronic stress induces similar behavioral effects in male and female mice despite sex-specific molecular adaptations in the nucleus accumbens.

Women are more likely than men to suffer from major depression and anxiety disorders, a fact that is thought to depend in part on sex differences in stress susceptibility. Consistent with this, several preclinical stress paradigms have been reported to exert differential effects in males vs. females. For example, several studies have reported that female rodents are susceptible to a subset of depression- and anxiety-like behaviors induced by six days of stress exposure while males remain largely resilient. The current study sought to evaluate the generalizability of this increased vulnerability of female mice to sub-chronic stressors by examining potential sex differences in response to a new five-day stress paradigm. In addition to measuring behavior, the current work also evaluated the effects of stress on the expression of several genes in the nucleus accumbens that have been suggested to underlie sex differences in behavioral responses to sub-chronic stress. The current results indicate that males and females exhibit mostly similar behavioral alterations after exposure to this new stress model, but several sex-specific molecular alterations were observed in the nucleus accumbens following stress. Overall, our data indicate that females do not exhibit a general increase in susceptibility to 'depression-' and 'anxiety-like' behaviors induced by sub-chronic stressors, and they could reflect an example of sexual convergence in which similar behavioral alterations occur in males and females despite sex-specific molecular changes.

The Effects of Brain Serotonin Deficiency on Responses to High Fat Diet in Female Mice.

Clinical studies have reported an increased risk of depression and anxiety disorders among individuals who are obese, and women are more likely than men to suffer from depression, anxiety, and obesity. However, the effects of obesity-promoting diets on depression- and anxiety-like behavior remain controversial. A recent study from our group used the tryptophan hydroxylase 2 (R439H) knock-in mouse line to evaluate the impact of genetic brain serotonin (5-HT) deficiency on behavioral responses to high fat diet (HFD) in male mice. That study indicated that chronic exposure to HFD induced pro-anxiety-like effects in the open field test and antidepressant-like effects in the forced swim test in wild-type males. Interestingly, the antidepressant-like effect of HFD, but not the anxiogenic effect, was blocked by brain 5-HT deficiency in males. The current work sought to repeat these studies in females. Our new data suggest that females are less susceptible than males to HFD-induced weight gain and HFD-induced alterations in behavior. In addition, the effects of chronic HFD on the expression of inflammation-related genes in the hippocampus were markedly different in females than we had previously reported in males, and HFD was shown to impact the expression of several inflammation-related genes in a genotype-dependent manner. Together, our findings highlight the importance of brain 5-HT and sex in regulating behavioral and molecular responses to HFD. Our results may have important implications for our understanding of the clinically observed sex differences in the consequences of obesity.

The Tulane accelerated physician training program (TAP-TP): A novel combination of scholarship and service.

INTRODUCTION: In spite of a projected shortage of physicians in the USA, the relatively long time and duration of training and high expense, the education of U.S. physicians has changed little over the past 120 years. METHODS: To address these issues, Tulane University developed a program, the Tulane accelerated physician training program (TAP-TP). This unique program allows selected Tulane undergraduate students to complete two years of undergraduate studies, followed by a mandatory year of public service, prior to four years of medical school. RESULTS: Students almost exclusively major in Cell and Molecular Biology (CMB), and used credits earned in Medical School to complete the required hours for their Bachelor's degree. The program was judged to be successful based on its ability to attract, retain, and graduate students into medical residency programs. The shortened time frame needed to complete the undergraduate program is associated with significant cost savings for the students. Educational outcomes were not statistically different between TAP-TP and traditional students despite the accelerated curriculum. CONCLUSIONS: TAP-TP is a unique model to graduate physicians in an accelerated fashion at significant cost savings.

Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR's pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3ß Phosphorylation in the Hippocampus.

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression- and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3ß phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.

Crises and Turnaround Management: Lessons Learned from Recovery of New Orleans and Tulane University Following Hurricane Katrina.

By their very nature both man-made and natural disasters are unpredictable, and so we recommend that all health-care institutions be prepared. In this paper, the authors describe and make a number of recommendations, regarding the importance of crisis and turnaround management using as a model the New Orleans public health system and Tulane University Medical School post-Hurricane Katrina. Leadership skills, articulation of vision, nimble decision making, and teamwork are all crucial elements of a successful recovery from disaster. The leadership team demonstrated courage, integrity, entrepreneurship, and vision. As a result, it led to a different approach to public health and the introduction of new and innovative medical education and research programs.

Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.

Simulated Interprofessional Education Discharge Planning Meeting to Improve Skills Necessary for Effective Interprofessional Practice.

PURPOSE OF STUDY: The purpose of this study was to evaluate the use of a simulation-enhanced interprofessional education (Sim-IPE) discharge planning learning experience using simulated patients (SPs), to explore the ability for students to communicate with each other and to a patient/caregiver, and to use clinical thinking to make a safe and appropriate interprofessional discharge recommendation. PRIMARY PRACTICE SETTING(S): Educational institution; university simulation center. METHODOLOGY AND SAMPLE: A Sim-IPE was performed with students from physical therapy (N = 46), nursing (N = 25), and social work (N = 11). Students were placed into interprofessional teams. Presimulation, each student was expected to complete a survey and review several items including the patient case, a communication strategy, and community resources. The team then interacted with SPs portraying the patient and the family member. Postsimulation, facilitators led a debriefing session and students completed a post-IPE survey. The Interprofessional Collaborative Competency Attainment Survey (ICCAS) was completed pre- and postexperience. RESULTS: Most students reported that they strongly or somewhat agreed that the experience improved their clinical thinking skills (67%; n = 55), improved awareness of the patient voice in shared decision-making (72.8%; n = 59), improved ability to prioritize patient's list of impairments (75.3%; n = 61), and improved confidence with discharge planning (69.1%; n = 56). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Discharge planning is inherently an interprofessional process. Utilizing a simulation as a method to practice discharge planning may have a positive impact on future clinical practice. Completing the ICCAS may not be the appropriate assessment when evaluating change before and after an IPE experience based on the high scores noted preexperience. The use of a simulated discharge planning meeting may improve skills necessary for effective interprofessional practice.

Brain-region-specific Molecular Responses to Maternal Separation and Social Defeat Stress in Mice.

The association between stress and mental illness has been well documented, but the molecular consequences of repeated exposure to stress have not been completely identified. The present study sought to elucidate the combinatorial effects of early-life maternal separation stress and adult social defeat stress on alterations in signal transduction and gene expression that have been previously implicated in susceptibility to psychosocial stress. Molecular analyses were performed in the prelimbic/infralimbic cortex, amygdala, and nucleus accumbens, three brain regions that have been suggested to play critical roles in determining stress responses. The current data reveal that both maternal separation and social defeat significantly impact the expression of genes involved in histone methylation and the ß-catenin-, endogenous opioid-, neurotrophin-, and glucocorticoid signaling pathways. Although the effects of maternal separation and social defeat were largely non-overlapping, a subset of genes in each brain region were governed by additive, opposing, or other types of interactions between these stress paradigms, thus highlighting potential molecular mechanisms through which these stressors might coordinately regulate brain function and behavior.

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD.

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75(NTR) directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75(NTR) or transplantation of p75(NTR)-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75(NTR) to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.

Two kinds of rule regulating human subjects research.

Alan Wertheimer argues that before we promulgate some rule regarding the conduct of research on human subjects we ethically ought to consider the consequences of the rule being followed. This ethical requirement has an exception, though, Wertheimer maintains: it doesn't apply to rules that are not motivated by considerations of outcome. I agree that there is an exception to be made to Wertheimer's proposed ethical requirement, but not Wertheimer's exception. The important distinction is not that between rules motivated by considerations of outcome and rules motivated otherwise, but between rules designed to enforce ethics and rules not so designed. Before we promulgate the latter kind of rule, we are ethically required to consider the consequences of doing so. This is not so for the former kind of rule. My exception, unlike Wertheimer's, yields the conclusion that we should promulgate, regardless of the consequences of doing so, a rule requiring that the potential benefit to the subject of participation in a study outweigh the risks. This rule is motivated by considerations of outcome, so it would land on the wrong side of Wertheimer's divide. But it's also designed to enforce ethics, so it lands on the correct side of my divide.

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.

Serotonin deficiency alters susceptibility to the long-term consequences of adverse early life experience.

Brain 5-HT deficiency has long been implicated in psychiatric disease, but the effects of 5-HT deficiency on stress susceptibility remain largely unknown. Early life stress (ELS) has been suggested to contribute to adult psychopathology, but efforts to study the long-term consequences of ELS have been limited by a lack of appropriate preclinical models. Here, we evaluated the effects of 5-HT deficiency on several long-term cellular, molecular, and behavioral responses of mice to a new model of ELS that combines early-life maternal separation (MS) of pups and postpartum learned helplessness (LH) training in dams. Our data demonstrate that this paradigm (LH/MS) induces depressive-like behavior and impairs pup retrieval in dams. In addition, we show that brain 5-HT deficiency exacerbates anxiety-like behavior induced by LH/MS and blunts the effects of LH/MS on acoustic startle responses in adult offspring. Although the mechanisms underlying these effects remain unclear, following LH/MS, 5-HT-deficient animals had significantly less mRNA expression of the mineralocorticoid receptor in the amygdala than wild-type animals. In addition, 5-HT-deficient mice exhibited reduced mRNA levels of the 5-HT2a receptor and p11 in the hippocampus regardless of stress. LH/MS decreased the number of doublecortin+ immature neurons in the hippocampus in both wild-type (WT) and 5-HT-deficient animals. Our data emphasize the importance of complex interactions between genetic factors and early life experience in mediating long-term changes in emotional behavior. These findings may have important implications for our understanding of the combinatorial roles of 5-HT deficiency, ELS, and postpartum depression in the development of neuropsychiatric disorders.

The "for-benefit" academic medical center: a solution for survival.

Academic medical centers (AMCs) are the backbone of the U.S. health care system. They provide a disproportionate share of charity care and serve as a training ground for future physicians. Yet, AMCs face profound economic challenges, from changes in funding to changes in the health care market. To survive, many AMCs will need to form integrated health systems, a process expected to cost tens, if not hundreds, of millions of dollars. Nearly all AMCs are structured as not-for- profit entities, which places restrictions on their ability to forge partnerships, pursue joint ventures, and access private capital, often essential elements for forming such integrated systems. An alternative model known as the "for-benefit" corporation can allow AMCs to retain their important social mission and the other advantages of their not-for-profit status while allowing them flexibility and access to both investment and philanthropic capital. To pursue the for-benefit pathway, AMCs have two options-either they could work within the constraints of existing laws to restructure themselves as for-benefit entities, or they could create, under federal law, a new for-benefit AMC model, allowing for the orderly conversion of not-for-profit AMCs. Essential components of a for-benefit AMC include a social purpose, access to multiple forms of capital, the use of earnings to support its purpose, transparency, aligned compensation, and tax exemptions. Restructuring an AMC as a for-benefit entity enables it to both advance shareholder value and further the public good.