Adverse Effects Related to Corticosteroid Use in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis.

OBJECTIVES: We postulate that corticosteroid-related side effects in critically ill patients are similar across sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). By pooling data across all trials that have examined corticosteroids in these three acute conditions, we aim to examine the side effects of corticosteroid use in critical illness. DATA SOURCES: We performed a comprehensive search of MEDLINE, Embase, Centers for Disease Control and Prevention library of COVID research, CINAHL, and Cochrane center for trials. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared corticosteroids to no corticosteroids or placebo in patients with sepsis, ARDS, and CAP. DATA EXTRACTION: We summarized data addressing the most described side effects of corticosteroid use in critical care: gastrointestinal bleeding, hyperglycemia, hypernatremia, superinfections/secondary infections, neuropsychiatric effects, and neuromuscular weakness. DATA SYNTHESIS: We included 47 RCTs (n = 13,893 patients). Corticosteroids probably have no effect on gastrointestinal bleeding (relative risk [RR], 1.08; 95% CI, 0.87-1.34; absolute risk increase [ARI], 0.3%; moderate certainty) or secondary infections (RR, 0.97; 95% CI, 0.89-1.05; absolute risk reduction, 0.5%; moderate certainty) and may have no effect on neuromuscular weakness (RR, 1.22; 95% CI, 1.03-1.45; ARI, 1.4%; low certainty) or neuropsychiatric events (RR, 1.19; 95% CI, 0.82-1.74; ARI, 0.5%; low certainty). Conversely, they increase the risk of hyperglycemia (RR, 1.21; 95% CI, 1.11-1.31; ARI, 5.4%; high certainty) and probably increase the risk of hypernatremia (RR, 1.59; 95% CI, 1.29-1.96; ARI, 2.3%; moderate certainty). CONCLUSIONS: In ARDS, sepsis, and CAP, corticosteroids are associated with hyperglycemia and probably with hypernatremia but likely have no effect on gastrointestinal bleeding or secondary infections. More data examining effects of corticosteroids, particularly on neuropsychiatric outcomes and neuromuscular weakness, would clarify the safety of this class of drugs in critical illness.

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors.

Background: Millions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors. Methods: Male and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms. Results: Long-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes. Conclusions: Corticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.

Corticosteroids in Sepsis and Septic Shock: A Systematic Review, Pairwise, and Dose-Response Meta-Analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to assess the efficacy and safety of corticosteroids in patients with sepsis. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Library, up to January 10, 2023. STUDY SELECTION: We included randomized controlled trials (RCTs) comparing corticosteroids with placebo or standard care with sepsis. DATA EXTRACTION: The critical outcomes of interest included mortality, shock reversal, length of stay in the ICU, and adverse events. DATA ANALYSIS: We performed both a pairwise and dose-response meta-analysis to evaluate the effect of different corticosteroid doses on outcomes. We used Grading of Recommendations Assessment, Development and Evaluation to assess certainty in pooled estimates. DATA SYNTHESIS: We included 45 RCTs involving 9563 patients. Corticosteroids probably reduce short-term mortality (risk ratio [RR], 0.93; 95% CI, 0.88-0.99; moderate certainty) and increase shock reversal at 7 days (RR, 1.24; 95% CI, 1.11-1.38; high certainty). Corticosteroids may have no important effect on duration of ICU stay (mean difference, -0.6 fewer days; 95% CI, 1.48 fewer to 0.27 more; low certainty); however, probably increase the risk of hyperglycemia (RR, 1.13; 95% CI, 1.08-1.18; moderate certainty) and hypernatremia (RR, 1.64; 95% CI, 1.32-2.03; moderate certainty) and may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01-1.45; low certainty). The dose-response analysis showed a reduction in mortality with corticosteroids with optimal dosing of approximately 260 mg/d of hydrocortisone (RR, 0.90; 95% CI, 0.83-0.98) or equivalent. CONCLUSIONS: We found that corticosteroids may reduce mortality and increase shock reversal but they may also increase the risk of hyperglycemia, hypernatremia, and neuromuscular weakness. The dose-response analysis indicates optimal dosing is around 260 mg/d of hydrocortisone or equivalent.

Forebrain Glucocorticoid Receptor Overexpression Alters Behavioral Encoding of Hippocampal CA1 Pyramidal Cells in Mice.

Glucocorticoid signaling influences hippocampal-dependent behavior and vulnerability to stress-related neuropsychiatric disorders. In mice, lifelong overexpression of glucocorticoid receptor (GR) in forebrain excitatory neurons altered exploratory behavior, cognition, and dorsal hippocampal gene expression in adulthood, but whether GR overexpression alters the information encoded by hippocampal neurons is not known. We performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female wild-type (WT) and GR-overexpressing (GRov) mice during exploration of a novel open field, where most CA1 neurons are expected to respond to center location and mobility. Most neurons showed sensitivity to center location and/or mobility based on single-neuron calcium amplitude and event rate, but these sensitivity patterns differed between genotypes. GRov neurons were more likely than WT neurons to display center sensitivity and less likely to display mobility sensitivity. More than one-third of these responsive GRov neurons were sensitive only to center location and not mobility, while uniquely center-sensitive neurons were rare in WT. Most center-sensitive neurons exhibited anticipatory activity, suggesting they could drive behavior. We conclude that, compared with wild-type, dorsal CA1 pyramidal cells in GRov mice preferentially respond to center location rather than mobility in a novel open field. Such changes in the information encoded by individual hippocampal neurons in an aversive environment could underlie changes in stress vulnerability because of genetic or epigenetic variations in glucocorticoid receptor signaling.

Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.

Glucocorticoids and the Brain after Critical Illness.

Treatment for critical illness typically focuses on a patient's short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut-brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.

Rapid response of Nelson's syndrome to pasireotide in radiotherapy-naive patient.

BACKGROUND: Nelson's syndrome is a well-described complication following bilateral adrenalectomy for management of Cushing's disease. There is no consensus on optimal management of Nelson's syndrome, characterized by the triad of pituitary corticotroph adenoma growth, elevated serum adrenocorticotropic hormone, and skin hyperpigmentation. Medical therapy with a variety of drug classes have been studied. One potentially promising drug already approved for Cushing's disease is pasireotide, a somatostatin analog with affinity for multiple somatostatin receptors, including subtype 5, the most highly expressed receptor on corticotroph tumors. CASE PRESENTATION: A 24-year-old female was diagnosed with Cushing's disease with initial ACTH levels around 700-800 pg/mL. She underwent transsphenoidal surgery without remission, followed by bilateral adrenalectomy. Over the subsequent 3 years, the patient developed skin hyperpigmentation, recurrent elevations of ACTH, and tumor recurrence requiring two additional transsphenoidal surgeries. After her third transsphenoidal resection, ACTH normalized, no residual tumor was seen on radiology, and the patient's skin hyperpigmentation improved. She then had an uncomplicated full-term pregnancy, during which ACTH levels remained within normal limits. One month after delivery, ACTH levels began rising to a peak at 5,935 pg/mL. Imaging revealed two new bilateral pituitary adenomas, measuring 14 mm on the left, and 7 mm on the right. She was then started on pasireotide. After two months of therapy, ACTH decreased to 609 pg/mL, and repeat pituitary MRI showed interval decrease in size of both pituitary adenomas to 13 mm on the left and 6 mm on the right. CONCLUSION: We report the protracted course of a young female with several recurrences of Nelson's syndrome following bilateral adrenalectomy and multiple transsphenoidal surgeries, who ultimately responded to pasireotide. Unique features of her case not described previously are the response to pasireotide in a radiotherapy-naive patient, as well as the rapid radiologic response to therapy. Her history illustrates the unresolved challenges of Nelson's syndrome and the continued need for additional studies to identify optimal management.

Sepsis survivor mice exhibit a behavioral endocrine syndrome with ventral hippocampal dysfunction.

Severe acute stressors are known to trigger mood disorders in humans. Sepsis represents one such stressor, and survivors often suffer long term from psychiatric morbidity. We hypothesized that sepsis leads to lasting changes in neural circuits involved in stress integration, altering affective behavior and the stress response. To investigate this hypothesis, sepsis was induced in male C57Bl/6 mice using cecal ligation and puncture (CLP), and control mice underwent sham surgery. Mice recovered from acute illness within 2 weeks, after which they exhibited increased avoidance behavior and behavioral despair compared with sham, with behavioral changes observed more than 5 weeks after recovery. Sepsis survivors also showed evidence of enhanced hypothalamic-pituitary-adrenal (HPA) axis activity, with increased corticosterone after a novel stressor and increased adrenal weight. In the brain, sepsis survivor mice showed decreased stress-induced cfos mRNA and increased glucocorticoid receptor immunoreactivity specifically in the ventral hippocampus, a brain region known to coordinate emotional behavior and HPA axis activity. We conclude that murine sepsis survivors exhibit a behavioral neuroendocrine syndrome of negative affective behavior and HPA axis hyperactivity, which could be explained by ventral hippocampal dysfunction. These findings could contribute to our understanding of the human post-intensive care syndrome.

Persistent Neuroinflammation and Brain-Specific Immune Priming in a Novel Survival Model of Murine Pneumosepsis.

Pneumonia is the leading cause of sepsis and septic shock. Patients who survive pneumonia are vulnerable to long-term complications including increased risk of neurocognitive dysfunction. This study investigated the immune response and long-term complications of a non-surgical mouse model of Klebsiella pneumoniae pneumosepsis with antibiotic treatment. Pneumosepsis resulted in acutely enhanced expression of inflammatory cytokines, chemokines, and damage-associated molecular patterns in the brain and spleen. Despite resolution of infection, murine pneumosepsis survivors demonstrated a deficit in exploratory locomotor behavior at 2 weeks. This was associated with brain-specific persistent inflammatory gene expression and infiltrating myeloid cells in the brain. The brain inflammatory response was also primed in response to secondary challenge with lipopolysaccharide. The findings of this study demonstrate behavioral and inflammatory outcomes that parallel observations in other models of sepsis, but that have not previously been described in antibiotic-treated pneumonia models, highlighting a common pathway to the development of chronic brain dysfunction in sepsis survival.

Glucocorticoids and resilience.

All organisms endure frequent challenges to homeostasis, or stressors, that require adaptation. Depending on the individual, the context, and the magnitude of stress, this active adaptation can lead to behavioral susceptibility or resilience. The latter is an under-appreciated consequence of stress, as the damaging effects of chronic stress and chronically elevated glucocorticoids have received much more attention. We suggest here that neural pathways promoting resilience are initiated at the time of stress, and that they involve glucocorticoid signaling. By focusing on the neurobiology of resilience induction and the identification of vulnerable individuals, we may be able to intervene in the future at the time of stress to promote positive adaptation.

S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.

Psychiatric Symptoms in Survivors of Acute Respiratory Distress Syndrome. Effects of Age, Sex, and Immune Modulation.

RATIONALE: Psychiatric morbidity after acute respiratory distress syndrome (ARDS) is common, and our current ability to predict psychiatric symptoms based on patient- and illness-specific factors is limited. OBJECTIVES: We assessed symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) in long-term survivors of ARDS, as well as the associated changes in cortisol levels. METHODS: The participants were enrolled in a randomized, double-blind, placebo-controlled trial of granulocyte macrophage-colony stimulating factor (GM-CSF) or placebo conducted at three academic medical centers. There were 132 patients enrolled, and 44 patients completed 6-month follow-up questionnaires (45% of survivors). RESULTS: Six months after enrollment, survivors completed the Post-Traumatic Stress Syndrome 10 Questions Inventory, Impact of Event Scale, and Hospital Anxiety and Depression Scale to assess psychiatric symptoms. Plasma cortisol levels during treatment were measured by immunoassay. Thirty-six percent of patients reported significant psychiatric symptoms on at least one scale. GM-CSF-treated patients reported more severe posttraumatic stress and depression symptoms than patients in the placebo group. In multiple regression analyses, younger age, female sex, higher severity of illness, fewer steroid treatment days, and GM-CSF treatment were all independently associated with more severe psychiatric symptoms on at least one scale. CONCLUSIONS: 6 months after ARDS, age, sex, illness severity, steroids, and GM-CSF treatment were associated with psychiatric symptom scores. These associations should be confirmed in a larger population. Clinical Trial registered with clinicaltrials.gov (NCT00201409).

House Staff Participation in Patient Safety Reporting: Identification of Predominant Barriers and Implementation of a Pilot Program.

OBJECTIVES: Patient safety event (PSE) reporting is a critical element for healthcare organizations that are striving for continuous quality improvement. Although resident physicians routinely provide the majority of direct patient care, the level of their participation in PSE reporting historically has been low. In addition, as part of the Accreditation Council for Graduate Medical Education's Next Accreditation System, the Clinical Learning Environment Review site visit assesses residents' engagement in PSE reporting at each accredited academic institution. The objective of this study was to understand the common barriers to PSE reporting and design an intervention to increase the number of PSE reports by resident physicians. METHODS: We surveyed 304 residents and fellows to assess attitudes toward the PSE reporting system and identify barriers to submitting online PSE reports. Based on this analysis of barriers, we piloted interventions with the internal medicine residency program and measured their effect on resident PSE reporting. RESULTS: Of the survey respondents, 58% had never submitted a PSE report. The most commonly identified barriers were too much time required to submit a report (38% of all respondents), lack of education on how or what to report (37%), lack of feedback or change after reporting (19%), and concern for repercussions or lack of anonymity (13%). Based on this analysis of barriers, we piloted interventions with the internal medicine residency program to educate residents about PSE reporting through a reminder message in their orientation e-mail, informational slides at the end of conferences that described what and how to report, a pocket card with reporting instructions, and leadership encouragement during walk rounds by chief medical residents and the program director. Compared with the 10 weeks before the start of the intervention, the number of PSE reports submitted by internal medicine residents more than doubled, from 16 to 37 reports (P < 0.01). This increase in resident PSE reporting was sustained for 20 weeks despite the interventions lasting only 8 weeks. CONCLUSIONS: A resident-driven intervention that fostered a culture of encouragement for PSE reporting through leadership support and targeted education increased the number of PSE reports submitted by internal medicine residents at our health system. Hospitals and health systems should seek to understand the common barriers to PSE reporting from this important group of direct patient care providers and administer structured educational programs to encourage their participation.

Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency.

CONTEXT: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. OBJECTIVES: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. PARTICIPANTS: The study enrolled eight classic 21OHD females, ages 18-58 years, seen at a single tertiary referral university setting. DESIGN: This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. RESULTS: Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. CONCLUSION: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.

Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway.

The opioid peptides, dynorphin (DYN) and enkephalin (L-ENK) are contained in the hippocampal mossy fiber pathway where they modulate synaptic plasticity. In rats, the levels of DYN and L-ENK immunoreactivity (-ir) are increased when estrogen levels are elevated (Torres-Reveron et al., 2008, 2009). Here, we used quantitative immunocytochemistry to examine whether opioid levels are similarly regulated in wildtype (WT) mice over the estrous cycle, and how these compared to males. Moreover, using estrogen receptor (ER) alpha and beta knock-out mice (AERKO and BERKO, respectively), the present study examined the role of ERs in rapid, membrane-initiated (6 h), or slower, nucleus-initiated (48 h) estradiol effects on mossy fiber opioid levels. Unlike rats, the levels of DYN and L-ENK-ir did not change over the estrous cycle. However, compared to males, females had higher levels of DYN-ir in CA3a and L-ENK-ir in CA3b. In WT and BERKO ovariectomized (OVX) mice, neither DYN- nor L-ENK-ir changed following 6 or 48 h estradiol benzoate (EB) administration. However, DYN-ir significantly increased 48 h after EB in the dentate gyrus (DG) and CA3b of AERKO mice only. These findings suggest that cyclic hormone levels regulate neither DYN nor L-ENK levels in the mouse mossy fiber pathway as they do in the rat. This may be due to species-specific differences in the mossy fiber pathway. However, in the mouse, DYN levels are regulated by exogenous EB in the absence of ERα possibly via an ERß-mediated pathway requiring new gene transcription.

Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice.

BACKGROUND: Most anxiety and depressive disorders are twice as common in women compared with men, and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and perimenopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain-derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Valine66Methionine [Val66Met]), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. METHODS: As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle-specific expression of anxiety-like behaviors. RESULTS: Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and, as adults, differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle-specifically, more anxiety-like behaviors during the estrus phase. CONCLUSIONS: These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans.

Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms.

From its origins in how the brain controls the endocrine system via the hypothalamus and pituitary gland, neuroendocrinology has evolved into a science that now includes hormone action on many aspects of brain function. These actions involve the whole central nervous system and not just the hypothalamus. Advances in our understanding of cellular and molecular actions of steroid hormones have gone beyond the important cell nuclear actions of steroid hormone receptors to include signaling pathways that intersect with other mediators such as neurotransmitters and neuromodulators. This has, in turn, broadened the search for and identification of steroid receptors to include nonnuclear sites in synapses, dendrites, mitochondria, and glial cells, as well as cell nuclei. The study of estrogen receptors and estrogen actions on processes related to cognition, mood, autonomic regulation, pain, and neuroprotection, among other functions, has led the way in this new view of hormone actions on the brain. In this review, we summarize past and current work in our laboratory on this topic. This exciting and growing field involving many laboratories continues to reshape our ideas and approaches to neuroendocrinology both at the bench and the bedside.