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Background Commercially available near infrared spectroscopy devices for continuous free flap tissue oxygenation (StO2) monitoring can only be used on flaps with a cutaneous component. Additionally, differences in skin quality and pigmentation may alter StO2 measurements. Here, we present a novel implantable heat convection probe that measures microvascular blood flow for peripheral monitoring of free flaps, and is not subject to the same issues that limit the clinical utility of near-infrared spectroscopy. Methods The intratissue microvascular flow-sensing device includes a resistive heater, 4 thermistors, a small battery, and a Bluetooth chip, which allows connection to a smart device. Convection of applied heat is measured and mathematically transformed into a measurement of blood flow velocity. This was tested alongside Vioptix T.Ox in a porcine rectus abdominis myocutaneous flap model of arterial and venous occlusion. After flap elevation, the thermal device was deployed intramuscularly, and the cutaneous T.Ox device was applied. Acland clamps were alternately applied to the flap artery and veins to achieve 15 minutes periods of flap ischemia and congestion with a 15 minutes intervening recovery period. In total, five devices were tested in three flaps in three separate pigs over 16 vaso-occlusive events. Results Flow measurements were responsive to both ischemia and congestion, and returned to baseline during recovery periods. Flow measurements corresponded closely with measured StO2. Cross-correlation at zero lag showed agreement between these two sensing modalities. Two novel devices tested simultaneously on the same flap showed only minor variations in flow measurements. Conclusion This novel probe is capable of detecting changes in tissue microcirculatory blood flow. This device performed well in a swine model of flap ischemia and congestion, and shows promise as a potentially useful clinical tool. Future studies will investigate performance in fasciocutaneous flaps and characterize longevity of the device over a period of several days.

Serial examination and direct measurement of intracompartmental pressure (ICP) are suboptimal strategies for the detection of acute compartment syndrome (CS) because they are operator-dependent and yield information that only indirectly reflects intracompartmental muscle perfusion. As a result, instances of unnecessary fasciotomy and unrecognized CS are relatively common. Recently, near-infrared spectroscopy (NIRS)-based systems for compartment monitoring have generated interest as an adjunct tool. Under ideal conditions, NIRS directly measures the oxygenation of intracompartmental muscle (StO

Background Current near-infrared spectroscopy (NIRS)-based systems for continuous flap monitoring are limited to flaps which carry a cutaneous paddle. As such, this useful and reliable technology has not previously been applicable to muscle-only free flaps where other modalities with substantial limitations continue to be utilized. Methods We present the first NIRS probe which allows continuous monitoring of local tissue oxygen saturation (StO2) directly within the substance of muscle tissue. This probe is flexible, subcentimeter in scale, waterproof, biocompatible, and is fitted with resorbable barbs which facilitate temporary autostabilization followed by easy atraumatic removal. This novel device was compared with a ViOptix T.Ox monitor in a porcine rectus abdominus myocutaneous flap model of arterial and venous occlusions. During these experiments, the T.Ox device was affixed to the skin paddle, while the novel probe was within the muscle component of the same flap. Results The intramuscular NIRS device and skin-mounted ViOptix T.Ox devices produced very similar StO2 tracings throughout the vascular clamping events, with obvious and parallel changes occurring upon vascular clamping and release. The normalized cross-correlation at zero lag describing correspondence between the novel intramuscular NIRS and T.Ox devices was >0.99. Conclusion This novel intramuscular NIRS probe offers continuous monitoring of oxygen saturation within muscle flaps. This experiment demonstrates the potential suitability of this intramuscular NIRS probe for the task of muscle-only free flap monitoring, where NIRS has not previously been applicable. Testing in the clinical environment is necessary to assess durability and reliability.

Purpose/aims The aim of this study was to explore the perceptions that experienced and highly specialized nurses have of the clinical nurse specialist (CNS) role through description of the registered nurses' (RNs') experiences. Design This study used a qualitative descriptive design. Methods Interviews were conducted with 6 RNs (2 managers, 1 chief nursing officer, 2 educators, and 1 clinician) and 32 RNs who participated in 5 focus groups. Participants were purposively sampled from intensive care units and emergency departments from 4 public and private hospitals. The analysis of the narratives and field notes used thematic content analysis. Results Common aspects of the CNS competencies and the experienced RN were recognized. These included direct patient care, assessment, and mentoring, with important differences in management, research, and coaching competencies. Conclusion The findings could facilitate the development of a master's program for the CNS in Chile. Formally recognizing the skills and clinical experiences of expert RNs may motivate nurses to pursue a master's degree that prepares them for advanced practice.

Background: Nerve transfers represent a new paradigm in the treatment of nerve injuries. Their current level of adoption among surgeons is unknown. This study evaluates the incidence of nerve transfers on case logs of board-eligible plastic surgeons over the past 14 years and surveys practicing nerve surgeons regarding their use of this technique. Methods: We queried the American Board of Plastic Surgery case log database for all nerve reconstruction Current Procedural Terminology codes from 2008 to 2021 and assessed trends and relationships between geographic region, examination year, and nerve transfer use. We surveyed nerve surgery professional societies to assess trends in practice, compared with a 2017 survey. Results: A total of 1959 nerve reconstruction cases were logged by 738 candidates from 2008 to 2021. Twelve percent of cases included nerve transfers. The proportion of nerve transfer codes ( Z = −11.57; P < .0001) and the proportion of candidates performing nerve transfers ( Z = −9.21, P < .0001) increased over the study period. Nerve transfers were associated with geographic region (χ2 = 25.826, P = .0002), with most cases performed in the Midwest (26.4%). A higher proportion of practicing nerve surgeons reported performing nerve transfers in this survey than in our 2017 survey (χ2 = 16.7, P < .001). Conclusions: There has been an increase in nerve transfers logged in the past 14 years by board-eligible plastic surgeons, as well as increased use among currently practicing nerve surgeons. Although nerve transfer use is increasing among both plastic and orthopedic surgeons, a greater proportion of nerve reconstructions include nerve transfers in the plastic surgery cohort.

In this poster, researchers based at a Mid-Atlantic university campus provide an understanding of their evaluative steps informing an adaptation of the Diversity Circles program to include a multigenerational component, supporting diversity across the lifespan. Project methods and analysis have been informed by critical theoretical frameworks, including feminist gerontology, that illuminate the invisibility of age, even in the context of intersectional work. Pilot feedback from five participants from a condensed program in an Adult Development and Aging course informed the interview approach. Post-program semi-structured interviews, with program participants, including students and older adults (n=7), and community stakeholders (n=18), provided feedback on diversity needs at the campus and in the surrounding community, as well as on program content and experience and opportunity for further curriculum integration of concepts of age-friendliness, ageism, and age-awareness. Stakeholders interviewed included community practicum liaisons, university advising and student affairs staff, faculty and staff previously engaging in diversity-related activities, university administrators, university personnel attending to enrollment matters, and staff and faculty interested in student-centered curriculum design. Semi-structured interviews were chosen for data collection because of their capacity to provide saturated data from a small, purposeful sample. Focused codes emergent from the interviews included both a) suggestions for curriculum adaptation and modification as well as the value of existing content and b) issues of age-friendliness and ageism more generally. The research team looks toward incorporating suggestions within their findings in an expansion of the program on their campus, and disseminating findings for the benefit of other campuses’ programs.

Continuous, real-time monitoring of perfusion after microsurgical free tissue transfer or solid organ allotransplantation procedures can facilitate early diagnosis of and intervention for anastomotic thrombosis. Current technologies including Doppler systems, cutaneous O2-sensing probes, and fluorine magnetic resonance imaging methods are limited by their intermittent measurements, requirements for skilled personnel, indirect interfaces, and/or their tethered connections. This paper reports a wireless, miniaturized, minimally invasive near-infrared spectroscopic system designed for uninterrupted monitoring of local-tissue oxygenation. A bioresorbable barbed structure anchors the probe stably at implantation sites for a time period matched to the clinical need, with the ability for facile removal afterward. The probe connects to a skin-interfaced electronic module for wireless access to essential physiological parameters, including local tissue oxygenation, pulse oxygenation, and heart rate. In vitro tests and in vivo studies in porcine flap and kidney models demonstrate the ability of the system to continuously measure oxygenation with high accuracy and sensitivity.

Objectives The relationship between fireworks and patient characteristics is not known. Our objective was to examine how severe fireworks-related injuries in children and teens compare to adults. Methods We conducted a retrospective case series (2005-2015) study of patients who sustained consumer fireworks-related injuries requiring hospital admission and/or operation at a single level 1 trauma/burn center. The distribution of race, use behavior, injury type, body region injured, and firework type was examined by age groups, 1 to 10 years, 11 to 17 years, and 18 years or older. Results Data from 294 patients 1 to 61 years of age (mean, 24 years) were examined. The majority (91%) were male. The proportion of injuries from different firework types varied by age, with rockets causing the highest proportion in children aged 1 to 10 years, homemade fireworks in those aged 11 to 17 years, and shells/mortars in adults 18 years or older. Compared with adults, children aged 1 to 10 years were more frequently American Indian/Alaska Native, Hispanic, or Asian than White. Compared with adults, children aged 1 to 10 years and 11 to 17 years were more frequently bystanders than active users. Compared with adults, children aged 1 to 10 years and 11 to 17 years had a greater proportion of burn and face injuries. Children aged 1 to 10 years had a decreased proportion of hand injuries. Three patients, 2 adults and 1 child aged 11 to 17 years, died. Conclusions Children, teens, and adults experience severe fireworks-related injuries differently, by demographic characteristics, injury patterns, and firework types. Tailored public health interventions could target safety messaging and injury prevention outreach efforts to reduce firework injuries among children and adolescents.

Background Current near-infrared spectroscopy (NIRS)-based systems for continuous flap monitoring are highly sensitive for detecting malperfusion. However, the clinical utility and user experience are limited by the wired connection between the sensor and bedside console. This wire leads to instability of the flap–sensor interface and may cause false alarms. Methods We present a novel wearable wireless NIRS sensor for continuous fasciocutaneous free flap monitoring. This waterproof silicone-encapsulated Bluetooth-enabled device contains two light-emitting diodes and two photodetectors in addition to a battery sufficient for 5 days of uninterrupted function. This novel device was compared with a ViOptix T.Ox monitor in a porcine rectus abdominus myocutaneous flap model of arterial and venous occlusions. Results Devices were tested in four flaps using three animals. Both devices produced very similar tissue oxygen saturation (StO2) tracings throughout the vascular clamping events, with obvious and parallel changes occurring on arterial clamping, arterial release, venous clamping, and venous release. Small interdevice variations in absolute StO2 value readings and magnitude of change were observed. The normalized cross-correlation at zero lag describing correspondence between the novel NIRS and T.Ox devices was >0.99 in each trial. Conclusion The wireless NIRS flap monitor is capable of detecting StO2 changes resultant from arterial vascular occlusive events. In this porcine flap model, the functionality of this novel sensor closely mirrored that of the T.Ox wired platform. This device is waterproof, highly adhesive, skin conforming, and has sufficient battery life to function for 5 days. Clinical testing is necessary to determine if this wireless functionality translates into fewer false-positive alarms and a better user experience.

Vascular pedicle thrombosis after free flap transfer or solid organ transplantation surgeries can lead to flap necrosis, organ loss requiring re-transplantation, or even death. Although implantable flow sensors can provide early warning of malperfusion and facilitate operative salvage, measurements performed with existing technologies often depend on extrinsic conditions such as mounting methods and environmental fluctuations. Furthermore, the mechanisms for fixing such probes to vascular or skeletal structures may disrupt the normal blood flow or cause unnecessary tissue damage. Requirements for wired connections to benchtop readout systems also increase costs, complicate clinical care and constrain movements of the patient. Here, we report a wireless, miniaturized flow sensing system that exploits sub-millimeter scale, multi-nodal thermal probes, with biodegradable barbs that secure the probes to the surrounding tissues in a manner that facilitates removal after a period of use. These smartphone-readable devices, together with experimentally validated analytical models of the thermal transport physics, enable reliable, accurate flow sensing in ways that are largely immune to variations in temperature and mechanical perturbations. In vivo demonstrations of this technology in porcine myocutaneous flap and kidney malperfusion models highlight the essential capabilities in microsurgical and transplantation-related biomedical application scenarios.

There are more than 2 dozen nerve entrapment syndromes in the body. Generally, these occur at sites of fibroosseous or fibromuscular tunnels. Any insult that leads to an increase in the size of the nerve or a decrease in the volume of the tunnel will cause compression. Resultant nerve ischemia sets off a cascade of events that lead to predictable clinical signs and symptoms. Here, we review the most common nerve entrapment syndromes and highlight their assessment and management. Specific clinical scenarios that require a high suspicion for nerve entrapment are highlighted.

Background: Free fibula flap (FFF) and medial femoral condyle (MFC) flap are commonly used for upper extremity osseous reconstruction, yet donor-site morbidity has never been systematically compared. Methods: Patients who underwent an FFF or MFC for upper extremity extra-carpal osseous reconstruction at 3 academic hand centers were retrospectively identified. Only patients who underwent reconstruction for a defect in which either flap type is routinely used or has been described in the literature were deemed eligible. Patients who agreed to participate were asked to complete the Lower Extremity Functional Scale (LEFS) and Lower Limb Core Scale (LLCS). The reported population norm median score of LEFS is 77 points. The LLCS population norm mean score is 90.52 points. Results: Twenty-one patients (10 MFC, 11 FFF) were enrolled. The median LEFS score for patients after MFC was 76 (interquartile range [IQR], 49-80) points and 75 (IQR, 56-79) points after FFF. The median LLCS score for patients after MFC was 96.4 (IQR, 87.9-100) points and 100 (IQR, 91-100) points after FFF. Median LEFS scores were slightly below the population norm, whereas median LLCS scores were above the norm for both FFF and MFC. All patients stated they would have the surgery again and that any dysfunction or pain in the leg was justified by the benefit in the arm. Conclusions: When considering whether to use an MFC or FFF for upper extremity reconstruction, both flap types appear to result in modest and comparable donor-site morbidity.

Background Transversus abdominis release is a novel approach for myofascial advancement in ventral hernia repair and has been hypothesized to have lower rates of wound complication than anterior component separation. Methods Patients who had a ventral hernia repair with either transversus abdominis release or minimally invasive anterior component separation from January of 2010 to January of 2016 were enrolled in this retrospective cohort study. Patient characteristics were collected through chart review. Primary outcomes were operative time and wound complications. Multiple linear/Poisson regression and Fisher's exact test were used to determine statistical significance. Results Of 142 patients analyzed, 75 subjects underwent Butler minimally invasive anterior component separation and 67 underwent transversus abdominis release. There were no differences in baseline characteristics between groups, except that the anterior component separation group had more immunosuppressed patients (35 percent versus 19 percent). Median operative time for anterior component separation was 6.3 hours versus 6.1 hours for transversus abdominis release (p = 0.6). Overall wound complications did not differ between the groups (p = 0.5). Compared with anterior component separation, transversus abdominis release had a similar incidence of seroma/hematoma (relative risk, 0.9; 95 percent CI, 0.5 to 1.7), wound infection (relative risk, 1.1; 95 percent CI, 0.5 to 2.2), and mesh infection (relative risk, 0.7; 95 percent CI, 0.2 to 3.4). Hernia recurrence was 12 percent for anterior component separation and 6 percent for transversus abdominis release (relative risk, 0.6; 95 percent CI, 0.2 to 1.7). Reoperation was required in 19 percent of anterior component separation and 12 percent of transversus abdominis release subjects (relative risk, 0.5; 95 percent CI, 0.2 to 1.2). Conclusions Transversus abdominis release patients had similar operative times, wound complications, reoperations, and hernia recurrences compared with Butler minimally invasive anterior component separation patients. This contemporary comparison helps inform operative decisions for reconstructive surgeons. Clinical question/level of evidence Therapeutic, III.

We have shown differing effects of glucocorticoid receptor (GR) deletion from the dorsal raphe nucleus (DRN) and locus coeruleus (LC) on depression-relevant behavior in male mice, but DRN GR deletion has not been tested in female mice. Female floxed GR mice were given DRN injections of AAV2/9 pseudotype viral vectors transducing Cre recombinase to produce DRN GR gene deletion (Cre) and compared with mice receiving DRN injections of AAV2/9 transducing green fluorescent protein (GFP). Social interaction, a measure of depression-like withdrawal, was unaffected by DRN GR deletion, but forced swim immobility, a measure of despair-like passivity, was reduced in female Cre vs. GFP mice. Behavioral effects were not attributable to changes in basal corticosterone or LC GR deletion. Combined with our prior studies, the current findings suggest that DRN GR have sex-independent effects to promote forced swim immobility, but influence social interaction only in male mice. Differential effects of DRN GR deletion in female mice may provide insight into the greater incidence of depression and specific depression symptoms in women.

Abnormal glucocorticoid levels can cause psychiatric symptoms ranging from depression to euphoria that have been implicated in mood disorders. My overarching hypothesis is that these opposing effects are mediated by glucocorticoid receptors (GR) in different brain regions. My laboratory has shown that GR in the serotonergic dorsal raphe nucleus (DRN) promote depression-like social and behavioral withdrawal in mice. We have also shown that GR in the DRN and noradrenergic locus coeruleus (LC) exhibit divergent regulation by antidepressants that have differential efficacy for depression subtypes with opposing abnormalities in glucocorticoids. The current study tested the hypothesis that LC GR would have effects opposite to those in the DRN by preventing rather than promoting social withdrawal. GR was deleted from LC NE neurons in female and male floxed GR mice by bilateral injections of lentivirus transducing Cre recombinase under control of a multimerized Phox 2a/2b response sequence (PRS) from the dopamine β-hydroxylase promoter (PRS-Cre). Female but not male PRS-Cre mice exhibited lower social interaction compared to controls injected with lentivirus transducing green fluorescent protein (PRS-GFP). Differences in social interaction between PRS-GFP and PRS-Cre females were not associated with differences in exploratory behavior, plasma corticosterone, male-female differences in LC GR expression, or changes in LC mineralocorticoid receptor or tyrosine hydroxylase gene expression. These results indicate that LC NE GR have sex-dependent effects to prevent social withdrawal, supporting the concept that glucocorticoids exert opposing effects on depression symptoms via different brain targets, and potentially revealing novel drug targets to treat depression, particularly in women.

The serotonergic dorsal raphe nucleus (DRN) expresses glucocorticoid receptors (GR), and systemic glucocorticoids have been shown to regulate expression and activity of tryptophan hydroxylase isoform 2, the rate-limiting enzyme for serotonin synthesis in brain. We have used intra-DRN injection of pseudotyped adeno-associated virus AAV2/9 transducing either green fluorescent protein (GFP control) or Cre recombinase (DRN GR deletion) in floxed GR mice to determine if DRN GR directly regulate DRN mRNA levels of tryptophan hydroxylase 2 (tph2). In a separate set of similarly-treated floxed GR mice, we also measured limbic forebrain region concentrations of serotonin (5-hydroxytryptamine; 5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). DRN GR deletion increased tph2 mRNA levels in the dorsal, lateral wing, and caudal parts of the DRN without altering tissue concentrations of 5-HT, 5-HIAA, or the 5-HIAA/5-HT ratio in limbic forebrain regions. We conclude that DRN GR inhibit DRN tph2 gene expression in mice without marked effects on serotonin metabolism, at least under basal conditions at the circadian nadir. These data provide the first evidence of localized control of DRN tph2 mRNA expression by DRN GR in mice.

Background There is a paucity of clinical data on severe fireworks-related injuries, and the relationship between firework types, injury patterns, and magnitude of impairment is not well understood. Our objective was to describe the relationship between fireworks type, injury patterns, and impairment. Methods Retrospective case series (2005–2015) of patients who sustained consumer fireworks-related injuries requiring hospital admission and/or an operation at a Level 1 Trauma/Burn Center. Fireworks types, injury patterns (body region, injury type), operation, and permanent impairment were examined. Results Data from 294 patients 1 to 61 years of age (mean 24 years) were examined. The majority (90%) were male. 119 (40%) patients were admitted who did not undergo surgery, 163 (55%) patients required both admission and surgery, and 12 (5%) patients underwent outpatient surgery. The greatest proportion of injuries was related to shells/mortars (39%). There were proportionally more rocket injuries in children (44%), more homemade firework injuries in teens (34%), and more shell/mortar injuries in adults (86%). Brain, face, and hand injuries were disproportionately represented in the shells/mortars group. Seventy percent of globe-injured patients experienced partial or complete permanent vision loss. Thirty-seven percent of hand-injured patients required at least one partial or whole finger/hand amputation. The greatest proportion of eye and hand injuries resulting in permanent impairment was in the shells/mortars group, followed by homemade fireworks. Two patients died. Conclusions Severe fireworks-related injuries from homemade fireworks and shells/mortars have specific injury patterns. Shells/mortars disproportionately cause permanent impairment from eye and hand injury.

This study describes the localization of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics, in the hypothalamus of Swiss Webster and C57BL/6J wild-type mice, leptin-deficient ob/ob mice, and leptin-resistant diet-induced obese (DIO) mice. The mice were given [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in 0.3% dodecyl maltoside by oral gavage. Once peak serum concentrations were reached, the mice received a lethal dose of pentobarbital and were subjected to intracardiac perfusion fixation. The brains were excised, post-fixed in paraformaldehyde, and cryo-protected in sucrose. Free-floating frozen coronal sections were cut at 25-µm and processed for imaging by immunofluorescence microscopy. In all four strains of mice, dense staining was concentrated in the area of the median eminence, at the base and/or along the inner wall of the third ventricle, and in the brain parenchyma at the level of the arcuate nucleus. These results indicate that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier and concentrate in an area of the hypothalamus known to regulate energy balance and glucose homeostasis. Most noteworthy is the localization of [D-Leu-4]-OB3 immunoreactivity within the hypothalamus of DIO mice via a conduit that is closed to leptin in this rodent model, and in most cases of human obesity. Together with our previous studies describing the effects of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on energy balance, glucose regulation, and signal transduction pathway activation, these findings are consistent with a central mechanism of action for these synthetic peptide leptin mimetics, and suggest their potential usefulness in the management of leptin-resistant obesity and type 2 diabetes in humans.

Recombinant adeno-associated virus vectors are an increasingly popular tool for gene delivery to the CNS because of their non-pathological nature, low immunogenicity, and ability to stably transduce dividing and non-dividing cells. One of the limitations of rAAVs is their preferential tropism for neuronal cells. Glial cells, specifically astrocytes, appear to be infected at low rates. To overcome this limitation, previous studies utilized rAAVs with astrocyte-specific promoters or assorted rAAV serotypes and pseudotypes with purported selectivity for astrocytes. Yet, the reported glial infection rates are not consistent from study to study. In the present work, we tested seven commercially available recombinant serotypes– rAAV1, 2, and 5 through 9, for their ability to transduce primary rat astrocytes [visualized via viral expression of green fluorescent protein (GFP)]. In cell cultures, rAAV6 consistently demonstrated the highest infection rates, while rAAV2 showed astrocytic transduction in some, but not all, of the tested viral batches. To verify that all rAAV constructs utilized by us were viable and effective, we confirmed high infectivity rates in retinal pigmented epithelial cells (ARPE-19), which are known to be transduced by numerous rAAV serotypes. Based on the in vitro results, we next tested the cell type tropism of rAAV6 and rAAV2 in vivo, which were both injected in the barrel cortex at approximately equal doses. Three weeks later, the brains were sectioned and immunostained for viral GFP and the neuronal marker NeuN or the astrocytic marker GFAP. We found that rAAV6 strongly and preferentially transduced astrocytes (>90% of cells in the virus-infected areas), but not neurons (∼10% infection rate). On the contrary, rAAV2 preferentially infected neurons (∼65%), but not astrocytes (∼20%). Overall, our results suggest that rAAV6 can be used as a tool for manipulating gene expression (either delivery or knockdown) in rat astrocytes in vivo.

This review highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, Colorado, June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. Jason Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo-pituitary-adrenocortical axis function in rat, highlighting emerging evidence for a critical role of this region in normal and pathological stress integration. Dr. Mohamed Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. Lauren Jacobson described studies using a mouse model to explore the diverse actions of antidepressant action in brain, suggesting mechanisms whereby antidepressants may be differentially effective in treating specific depression endophenotypes. Dr. Rachel Yehuda discussed the role of glucocorticoids in post-traumatic stress disorder (PTSD), indicating that low cortisol may be a trait that predisposes the individual to development of the disorder. Furthermore, she presented evidence indicating that traumatic events can have transgenerational impact on cortisol reactivity and development of PTSD symptoms. Together, the symposium highlighted emerging themes regarding the role of brain reorganization, individual differences and epigenetics in determining stress plasticity and pathology.

Although glucocorticoid feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis is frequently impaired in depression, atypical depression may exhibit increased feedback sensitivity. Because monoamine oxidase inhibitors (MAOI) are often more effective than tricyclic antidepressants (TCA) for atypical depression, we hypothesized that to normalize HPA function in atypical depression, MAOI would differ from TCA in decreasing rather than increasing feedback sensitivity. Consistent with this hypothesis and prior evidence for opposing effects on HPA feedback in mice, we report contrasting effects of chronic MAOI (phenelzine) and TCA (imipramine) treatment on neural corticosteroid receptor gene expression in adrenalectomized male C57BL/6 mice with fixed glucocorticoid levels. Our findings corroborate prior reports of antidepressant-induced increases in hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) expression. However, hippocampal effects were neither sustained nor representative of effects in other brain regions. Imipramine typically increased and phenelzine decreased GR expression in other feedback-related brain regions such as the paraventricular hypothalamus and prefrontal cortex. Imipramine effects were limited to feedback-related regions, whereas phenelzine had additional effects to decrease accumbens GR and central amygdala MR expression. Our results suggest an expansion of the corticosteroid receptor hypothesis of depression to include drug- and brain region-specific actions of antidepressants to decrease as well as increase corticosteroid receptor expression and feedback sensitivity. Our findings further suggest how antidepressants could improve glucocorticoid regulation of HPA activity without also facilitating the adverse effects of glucocorticoids on mood.

Stressful events before or just after parturition alter the subsequent phenotypical response to stress in a general process termed programming. Hypoxia during the period before and during parturition, and in the postnatal period, is one of the most common causes of perinatal distress, morbidity, and mortality. We have found that perinatal hypoxia (prenatal day 19 to postnatal day 14) augmented the corticosterone response to stress and increased basal corticotrophin-releasing hormone (CRH) mRNA levels in the parvocellular portion of the paraventricular nucleus (PVN) in 6-month-old rats. There was no effect on the levels of hypothalamic parvocellular PVN vasopressin mRNA, anterior pituitary pro-opiomelanocortin or CRH receptor-1 mRNA, or hippocampus glucocorticoid receptor mRNA. We conclude that hypoxia spanning the period just before and for several weeks after parturition programmes the hypothalamic-pituitary-adrenal axis to hyper-respond to acute stress in adulthood, probably as a result of drive from the parvocellular CRH neurones.

The objective of this study was to determine the effects of manipulating glucocorticoid negative feedback on acute ACTH and corticosterone responses to corticotropin-releasing hormone (CRH) injection in 7-day-old rats exposed to normoxia or hypoxia from birth. Chemical adrenalectomy was achieved with aminoglutethimide, and glucocorticoids were replaced with a low dose of dexamethasone. Hypoxia per se increased basal plasma corticosterone and attenuated the plasma ACTH response to CRH. Aminoglutethimide per se decreased plasma corticosterone and strongly increased basal plasma ACTH and anterior pituitary POMC gene expression. Dexamethasone partially attenuated elevations in basal plasma ACTH due to aminoglutethimide in both normoxic and hypoxic pups, but inhibited anterior pituitary POMC expression and CRH-induced plasma ACTH only in hypoxic pups. Despite this inhibition, hypoxic pups treated with both dexamethasone and aminoglutethimide still exhibited a significant CRH-induced increment in plasma ACTH, which was lacking in hypoxic pups not treated with either dexamethasone or aminoglutethimide. We conclude that ACTH responses to acute stimuli in hypoxic neonatal rats are prevented by ACTH-independent increases in corticosterone, rather than by intrinsic hypothalamic–pituitary hypoactivity.

Glucocorticoids have been implicated in hypoglycemia-induced autonomic failure but also contribute to normal counterregulation. To determine the influence of normal and hypoglycemia-induced levels of glucocorticoids on counterregulatory responses to acute and repeated hypoglycemia, we compared plasma catecholamines, corticosterone, glucagon, and glucose requirements in male wild-type (WT) and glucocorticoid-deficient, corticotropin-releasing hormone knockout (CRH KO) mice. Conscious, chronically cannulated, unrestrained WT and CRH KO mice underwent a euglycemic (Prior Eu) or hypoglycemic clamp (Prior Hypo) on day 1 followed by a hypoglycemic clamp on day 2 (blood glucose both days, 65 ± 1 mg/dl). Baseline epinephrine and glucagon were similar, and norepinephrine was elevated, in CRH KO vs. WT mice. CRH KO corticosterone was almost undetectable (

Hypoglycemia-induced counterregulatory failure is a dangerous complication of insulin use in diabetes mellitus. Controlled hypoglycemia studies in gene knockout models, which require the use of mice, would aid in identifying causes of defective counterregulation. Because stress can influence counterregulatory hormones and glucose homeostasis, we developed glucose clamps with remote blood sampling in conscious, unrestrained mice. Male C57BL/6 mice implanted with indwelling carotid artery and jugular vein catheters were subjected to 2 h of hyperinsulinemic glucose clamps 24 h apart, with a 6-h fast before each clamp. On day 1, blood glucose was maintained (euglycemia, 178 ± 4 mg/dl) or decreased to 62 ± 1 mg/dl (hypoglycemia) by insulin (20 mU·kg−1·min−1) and variable glucose infusion. Donor blood was continuously infused to replace blood sample volume. Baseline plasma epinephrine (32 ± 8 pg/ml), corticosterone (16.1 ± 1.8 μg/dl), and glucagon (35 ± 3 pg/ml) were unchanged during euglycemia but increased significantly during hypoglycemia, with a glycemic threshold of ∼80 mg/dl. On day 2, all mice underwent a hypoglycemic clamp (blood glucose, 64 ± 1 mg/dl). Compared with mice that were euglycemic on day 1, previously hypoglycemic mice had significantly higher glucose requirements and significantly lower plasma glucagon and corticosterone ( n = 6/group) on day 2. Epinephrine tended to decrease, although not significantly, in repeatedly hypoglycemic mice. Pre- and post-clamp insulin levels were similar between groups. We conclude that counterregulatory responses to acute and repeated hypoglycemia in unrestrained, chronically cannulated mice reproduce aspects of counterregulation in humans, and that repeated hypoglycemia in mice is a useful model of counterregulatory failure.

As befits a system essential for survival, neuroendocrine regulation of the hypothalamic--pituitary--adrenocortical (HPA) axis is characterized by tight control as well as plasticity. Stimulus-specific afferents code for specific hypothalamic corticotropin (ACTH) secretagogues, which have combinatorial effects on ACTH secretion, resulting in a glucocorticoid response that is tailored to stimulus intensity. Chronic stress-induced stimulation of HPA activity alters ACTH secretagogue expression and hypothalamic afferent activity to maintain adrenocortical responsiveness. Rigorous control of circadian HPA activity optimizes the balance between beneficial and adverse effects of glucocorticoids (largely mediated by glucocorticoid receptors) by minimizing circadian nadir glucocorticoid secretion (an effect mediated by mineralocorticoid receptors). HPA activity also is controlled by other glucocorticoid-regulated factors, such as immune and metabolic status. Dysregulation of these control mechanisms is likely to contribute to a variety of diseases.

Hypoxia is a common cause of neonatal morbidity and mortality. We have previously demonstrated a dramatic ACTH-independent activation of adrenal steroidogenesis in hypoxic neonatal rats, leading to increases in circulating corticosterone levels. The purpose of the present study was to determine if this ACTH-independent increase in corticosterone inhibits the ACTH response to acute stimuli. Neonatal rats were exposed to normoxia (control) or hypoxia from birth to 5 or 7 days of age. At the end of the exposure, plasma ACTH and corticosterone were measured before and after either ether vapors were administered for 3 min or CRH (10 μg/kg) was given intraperitoneally. Thyroid function, pituitary pro-opiomelanocortin (POMC) mRNA and ACTH content, and hypothalamic corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), and AVP mRNA were also assessed. Hypoxia led to a significant increase in corticosterone without a large increase in ACTH, confirming previous studies. The ACTH responses to ether or CRH administration were almost completely inhibited in hypoxic pups. Hypoxia did not affect the established regulators of the neonatal hypothalamic-pituitary-adrenal axis, including pituitary POMC or ACTH content, hypothalamic CRH, NPY, or AVP mRNA (parvo- or magnocellular), or thyroid function. We conclude that hypoxia from birth to 5 or 7 days of age leads to an attenuated ACTH response to acute stimuli, most likely due to glucocorticoid negative feedback. The neural and biochemical mechanism of this effect has yet to be elucidated.

Midlife weight gain occurs in many species, suggesting that leptin signaling is impaired at middle age. To test this hypothesis, we measured changes in food intake and body composition in young (Y) and middle-aged (MA) C57BL/6 male mice infused subcutaneously with phosphate-buffered saline or leptin. Leptin-induced decreases in food intake and body fat were delayed in MA mice and associated with catabolism after longer treatment periods. Endogenous plasma leptin levels did not correlate with body fat in MA mice. Calorie restriction (CR) reduced body fat, plasma leptin, and insulin in MA mice to levels in Y mice but did not upregulate leptin sensitivity. CR mice did not respond to leptin doses that inhibited food intake in MA mice and reduced food intake and body fat in Y mice significantly below levels in CR mice. Plasma corticosterone was significantly higher in leptin-treated CR vs. MA mice. We conclude that MA C57BL/6 mice exhibit impaired leptin signaling and that CR, possibly by elevating glucocorticoids, impairs appetite control without improving the metabolic actions of leptin.

Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects.

Delivery of genes to various brain regions can be accomplished using serotype 2 of the adeno-associated virus (AAV). Pseudotype AAV2 vectors, composed of the AAV2 genome packaged in the capsid of an alternative serotype, have increased efficiency of viral transduction. Transduction of pseudotype AAV2 vectors depends on cell type, brain region and stage of development. The dorsal raphé nucleus (DRN) and median raphé provides the majority of serotonin to forebrain regions and are implicated in the pathology and treatment of depression and anxiety. Viral vector technology in combination with stereotaxic surgery in mice provides a means to differentiate gene function in the DRN compared to the median raphé nucleus.Since AAV transduction efficiency has not yet been characterized for the DRN, we tested if AAV2 pseudotypes are more efficient than a standard serotype (AAV2/2) in transducing DRN cells in adult male mice on a C57BL/6J background.Although transduction did not differ significantly among vectors by 15 days post-injection, pseudotype AAV2/9 and AAV2/rh.10 vectors achieved significantly greater transduction of the DRN than did AAV2/2 and AAV2/1 vectors by 30 days post-injection. Pseudotypes AAV2/1 and AAV2/5 tended, although not significantly, to transduce DRN cells more efficiently than did AAV2/2.At the same titer, all pseudotype AAV tested tended to transduce the DRN more efficiently than standard AAV2/2 serotype at 30 days post-injection.Our results support the use of pseudotype AAV2/9 and AAV2/rh.10 for studying gene deletion or overexpression in the DRN.

Evidence of aberrant hypothalamic-pituitary-adrenocortical (HPA) activity in many psychiatric disorders, although not universal, has sparked long-standing interest in HPA hormones as biomarkers of disease or treatment response. HPA activity may be chronically elevated in melancholic depression, panic disorder, obsessive-compulsive disorder, and schizophrenia. The HPA axis may be more reactive to stress in social anxiety disorder and autism spectrum disorders. In contrast, HPA activity is more likely to be low in PTSD and atypical depression. Antidepressants are widely considered to inhibit HPA activity, although inhibition is not unanimously reported in the literature. There is evidence, also uneven, that the mood stabilizers lithium and carbamazepine have the potential to augment HPA measures, while benzodiazepines, atypical antipsychotics, and to some extent, typical antipsychotics have the potential to inhibit HPA activity. Currently, the most reliable use of HPA measures in most disorders is to predict the likelihood of relapse, although changes in HPA activity have also been proposed to play a role in the clinical benefits of psychiatric treatments. Greater attention to patient heterogeneity and more consistent approaches to assessing treatment effects on HPA function may solidify the value of HPA measures in predicting treatment response or developing novel strategies to manage psychiatric disease.

Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphe nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Because we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic-pituitary-adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 21 days of social defeat or control handling and were tested for anxiety-like behavior (open-field test, elevated-plus maze), depression-like behavior [sucrose preference, forced-swim test (FST), tail-suspension test (TST)], social interaction, and circadian and stress-induced HPA activity. DRN GR deletion decreased anxiety-like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair-like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral (an empty box) targets was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress-induced HPA activity without strongly altering circadian HPA activity. We have shown a novel role for DRN GR to mediate anxiety- and despair-like behavior and to regulate HPA negative feedback during acute stress.

Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic-pituitary-adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock-down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response.

A review of the generation and characterization of corticotropin-releasing hormone (CRH)-deficient mice is presented. The studies summarized demonstrate the central role of CRH in the pituitary-adrenal axis response to stress, circadian stimulation, and glucocorticoid withdrawal. Additionally, pro-inflammatory actions of CRH at sites of local inflammation are given further support. In contrast, behavioral effects during stress that had been ascribed to CRH action are not altered in CRH-deficient mice. The normal behavioral response to stress in CRH-deficient mice strongly suggests the importance of other, possibly as yet undiscovered, CRH-like molecules.

CRH is thought to play a role in responses of the adrenocortical and adrenomedullary systems during stress. To investigate the role of CRH in stress-induced secretions of corticosterone and epinephrine, we subjected wild-type (WT) and CRH-deficient (knockout, KO) mice to restraint, and analyzed plasma corticosterone, plasma catecholamines, and adrenal phenylethanolamine N-methyltransferase (PNMT) gene expression and activity before and during 3 h of restraint. Plasma corticosterone increased over 40-fold in WT mice, but minimally in CRH KO mice. Adrenal corticosterone content tended to increase in CRH KO mice, although to levels 5-fold lower than that in WT mice. CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint. Adrenal PNMT messenger RNA content in CRH KO mice tended to be lower than that in WT mice, though the degree of induction was similar in both genotypes. PNMT enzyme activity was significant...

Many studies have implicated corticotropin-releasing hormone (CRH) as a mediator of stress-induced decreases in food intake. However, urocortin, sauvagine, and urotensin, other members of the family of CRH-like molecules, have also been shown to be potent inhibitors of food intake. This raises the possibility that a CRH-related molecule might also be responsible for stress-induced anorexia. We therefore examined the effects of three chronic stressors, repetitive daily restraint, turpentine abscess, and surgical stress, upon food intake in wildtype and CRH-deficient mice created by targeted inactivation of the CRH gene. We have found that both genotypes have similar basal food intake which initially decreases to the same degree following initiation of each stress paradigm. Food intake also recovers following the same time course and to the same degree in both genotypes. Therefore, CRH is not necessary for decreases in food-intake induced by the chronic stressors examined in this study.

To determine if CRH and glucocorticoids are respectively required for hypophagia and catabolism in malnutrition, we have subjected wild-type (WT) and CRH knockout (KO) mice to dietary protein deprivation. Compared with WT mice, CRH KO mice exhibited greater decreases in food intake and negligible change in plasma corticosterone after 7 days of protein-free diet. Restricting consumption of normal or protein-free diet for 9 days to the lower intake in protein-deprived CRH KO mice increased evening plasma corticosterone in WT but not KO mice. Restricted intake of protein-free diet increased morning corticosterone more in both genotypes than restricted intake of normal diet, although corticosterone levels were much lower in CRH KO mice. CRH deficiency attenuated body and thymus weight loss induced by restricted diets. Lower weight loss in CRH KO mice was associated with lower fractional loss of body water and protein. The remaining catabolic response in CRH KO mice did not correlate with morning plasma catecholamines or insulin. Corticosterone, but not the progestational appetite stimulant megestrol acetate, prevented hypophagia in CRH KO mice given protein-free diet. We conclude that differences in feeding and metabolic responses to protein deprivation between WT and CRH KO mice are primarily attributable to glucocorticoid insufficiency.

There is considerable evidence that CRH can suppress food intake. As hypothalamic CRH, a main site of CRH expression, is also negatively regulated by glucocorticoids, it is unclear whether anorexia and weight loss in adrenal insufficiency are attributable to elevated CRH or to decreased glucocorticoid levels. To distinguish these possibilities, we have measured food intake and body weight in wild-type and CRH-deficient mice after sham adrenalectomy (Sham ADX) or adrenalectomy (ADX) with and without corticosterone (B) replacement. CRH deficiency neither increased basal food intake and body weight nor attenuated decreases in food intake after ADX or Sham ADX. B replacement producing plasma levels above the circadian peak completely blocked ADX-induced decreases in feeding and body weight in all mice and frequently stimulated food intake in CRH-deficient mice. Plasma levels of insulin and leptin, two other hormones involved in appetite regulation, did not differ between genotypes; however, the relationship between food intake and circulating leptin was significantly less negative at B doses that preserved appetite. B replacement levels slightly below circadian peak concentrations did not prevent hypophagia after ADX. We conclude that factors other than or in addition to CRH are more important in mediating appetite responses to adrenalectomy.

The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.

The generation of transgenic mice by introduction of intact or altered genes into the pronuclei of fertilized oocytes has proven a powerful tool in elucidating the consequences of ectopic or tissue-appropriate overproduction of a given gene product; in defining DNA elements responsible for gene-specific patterns of temporal, spatial, and regulated transcription; and in targeted oncogenesis for the development of cell culture lines for detailed in vitro study. This technology, however, has had limited success in addressing the role and essential function of specific peptides in the intact organism, except in the circumstance in which dominant negative alleles, capable of abrogating function of the normal allele, are available.1,2 With the establishment of embryonic stem (ES) cell culture systems amenable to in vitro manipulation for introduction of mutated genes, methods for selection of relatively rare homologous recombination events, and most importantly, the sustained capacity of these ES cells to contribute to the germline of chimeric mice, a method of addressing the consequences of loss of gene function has emerged.3,5 Targeted gene inactivation in ES cells with subsequent generation of deficient mice yields inheritable, complete loss of function at all stages of development and in all tissues. This is an advantage when assessing ontogenic importance, ability of interacting systems to compensate for loss of function, and the effects of chronic deficiency. These factors can also impair whole-organism analysis of function, inasmuch as chronic deficiency may allow up-regulation of compensatory systems, masking the in vivo function of the mutation, and global deficiency may make characterization at a specific site of synthesis difficult to determine. Most severely, loss of expression at all stages of development may lead to organism inviability.

Activity of the hypothalamic–pituitary–adrenocortical (HPA) axis is often abnormal in depression and could hold clues for better treatment of this debilitating disease. However, it has been difficult to use HPA activity as a depression biomarker because both HPA hyperactivity and HPA hypoactivity have been reported in depression. Melancholic depression has typically been associated with HPA hyperactivity, while atypical depression has been linked with HPA hypoactivity. Many animal models of chronic stress recapitulate behavioral aberrations and elevated HPA activity that could represent a model for melancholic depression. However, there are no animal models that could be used to elucidate the etiology or treatment of atypical depression. We have used repeated social defeat in mice to test the hypothesis that this chronic stress would induce dysphoria-like behavior associated with HPA hypoactivity in a subset of subjects. Intruder mice were placed in the home cage of an aggressive resident mouse for 5 min/d for 30 days. The majority of intruder mice had elevated basal plasma corticosterone (High Morning Corticosterone, or HMC) and adrenal 11β hydroxylase mRNA levels relative to control mice that were handled daily. However, a subset of intruder mice (Low Morning Corticosterone; LMC) exhibited basal plasma corticosterone and 11β hydroxylase mRNA levels that were indistinguishable from control levels. Significant changes in emotional behavior only occurred in LMC mice, which exhibited anxiety-like increases in activity and defecation during tail suspension and anhedonia-like decreases in sucrose preference. Relative to HMC mice, LMC mice also showed increases in gene expression of mineralocorticoid receptor in CA2 hippocampus, consistent with the possibility that HPA activity in this group is constrained by increased sensitivity to glucocorticoid negative feedback. LMC mice also exhibited increased c-fos gene expression compared to HMC mice in the paraventricular hypothalamus and lateral septum suggesting that central pathways fail to habituate to chronic stress even though adrenocortical activity is not stimulated. We conclude that LMC mice showed adrenocortical hyporesponsiveness, which in combination with the behavioral abnormalities in this group may represent a model for the HPA hypoactivity associated with atypical depression.