66 The amygdala plays a pivotal role in coordinating the behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in rats. In a fear-conditioning paradigm, pretraining amygdala lesions blocked freezing behavior, ultrasonic vocalizations, adrenocortical activation, and dopaminergic metabolic activation in the medial prefrontal cortex (mPFC). Posttraining lesions blocked mPFC dopamine, serotonin (5-hydroxytryptaminc [5-HT]), and NA activation and stress-induced freezing and defecation, and greatly attenuated adrenocortical

activation.67 The amygdala and positive reinforcement and attention The role of the amygdala is #4-mu mouse keyword# not limited to fear-conditioning and the processing of

aversive stimuli. Studies in rats using food-motivated associative learning indicate that the Inhibitors,research,lifescience,medical basolateral amygdala may be involved in the acquisition and representation of positive reinforcement values (possibly through its connections with the ventral striatal dopamine systems and the orbitofrontal cortex).68 Therefore, the amygdala is probably a key structure Inhibitors,research,lifescience,medical for the integration of behavior in conflicting situations, when both potentially rewarding and aversive stimuli are present. Recent studies indicate that the human amygdala can also process both positively and negatively valenced stimuli.69 Recent studies also indicate that the CeA may contribute to attentional function in conditioning, by way of its influence on basal forebrain cholinergic systems and on the dorsolateral striatum.68 The amygdala and social behavior and phobia The amygdala may play an important role in regulating social behavior. Thus, in adult macaque monkeys, selective

bilateral lesions of the amygdala result in a Inhibitors,research,lifescience,medical lack of fear response to inanimate objects and a “socially uninhibited” Inhibitors,research,lifescience,medical pattern of behavior.70 The amygdala may function as a protective “brake” during evaluation of a potential threat, and it has been suggested that social anxiety may involve a dysregulation or hyperactivity of the amygdala evaluative process.70 Studies in rats also suggest that the basolateral nucleus of the amygdala may play a crucial role in the consolidation of information that leads to the formation of a specific phobia.71 The extended amygdala Terminal deoxynucleotidyl transferase (BNST) and anxiety Although the amygdala is clearly involved in conditioned fear, its role in anxiety is less evident, because it is often difficult to specify the stimuli that triggers anxiety.72,73 Thus, lesions of the rat amygdala that suppressed fearelicited startle or freezing behavior did not affect measures of anxiety in the elevated plus-maze and shock-probe-burying tests, two classic tests of anxiety for rodents.74 Moreover, diazepam was effective in these tests, even in amygdala-lesioned rats, suggesting that the anxiolytic effects of benzodiazepines are not necessarily mediated by the amygdala.

2 The syndromal heterogeneity of the diagnostic constructs makes it impossible to demonstrate a potential

syndromal specificity of a drug. Historically, drugs have been developed H 89 mw empirically on the basis of clinical observations. The discovery of chlorpromazinc for the treatment of schizophrenia in the early fifties by Delay and Deniker,3 and of imipramine for depression a few years later by Kuhn4 are such examples. On the other hand, new psychopathological syndromes have been identified by observant clinicians who recognized the unique actions of psychotropic drugs like clomipramine for the treatment of specific disorders such as obsessive-compulsive disorder (OCD)5 or imipramine for panic disorders.6,7 Unlike other medical Inhibitors,research,lifescience,medical conditions, the etiology and pathophysiology of psychiatric disorders

remain unknown. This is true despite the recent advances in the understanding of the function Inhibitors,research,lifescience,medical of the central nervous system (CNS) and in the field of biological psychiatry. Neurotransmitter imbalances in some areas of the CNS as well as neuroanatomical and neurophysiological abnormalities have been hypothesized to explain most of these psychiatric disorders, but this hypothesis has failed to be conclusively demonstrated. However, as no rational alternative explanation has been advanced for these disorders, the current pharmacological approach to Inhibitors,research,lifescience,medical the treatment of psychiatric disorders is based Inhibitors,research,lifescience,medical on trying to restore the observed dysfunction of central neurotransmitters. Since the ICD-10 and DSM-IV classifications are based on clinical descriptions, they neglect biochemical and physiological

abnormalities that are involved in the pathogenesis of disorders. The increasing knowledge of transmitter function in relation to behavioral pharmacology has suggested links to numerous psychiatric conditions. This “pathophysiological approach” to Inhibitors,research,lifescience,medical the development of new treatments is oriented more toward behavioral abnormalities than toward nosological syndromes. Pathophysiological approaches allow transnosological treatment because particular symptoms can occur in many different psychiatric disorders. Behavioral abnormalities can be attributed to increased or decreased neuronal activity, and sometimes to alterations of specific transmitter receptors. This points to a role for functional pharmacology, which implies that, rather than nosological categories, one should treat basic disturbances in cognitive functions, also impulse control, perception, information processing, and mood regulation. Since in many cases monotherapy is insufficient to adequately treat the different nosological categories, naturalistic clinical practice requires that most patients be treated according to their symptoms with more than one drug.2 The need for such multiple-drug therapy is due to many factors, such as multiple syndromes, comorbidity, and different target symptoms like negative and positive symptoms in schizophrenia.

Finally, long-term or maintenance treatment of late-life anxiety with medication has not been studied (although we are currently carrying out a study of maintenance effects of SSRI treatment in late-life GAD), and no augmentation strategies can be recommended with confidence. Combining medication and psychotherapy for late-life anxiety disorders The inadequacy of Inhibitors,research,lifescience,medical monotherapy is well known in mood and anxiety disorders, and combination treatments may be more effective.179 Antidepressants and CBT

have different mechanisms and may be able to treat different components of the illness.180,181 Combination treatment in older adults might best be carried out sequentially, rather than simultaneously initiated,

to maximize costeffectiveness and allow the patient and provider to focus sequentially on different aspects of Inhibitors,research,lifescience,medical treatment, rather than divide focus among multiple treatments and components of illness at once.182 The hope is that, with two treatments targeting the different facets of the illness, persistent residual features and relapse are less likely. Supporting this assertion, a recent review of meta-analyses concluded that psychotherapies involving Inhibitors,research,lifescience,medical cognitive and behavioral strategies for GAD are superior to nondirective therapy and pill placebo, and equivalent to pharmacotherapy in the acute phase of treatment, with Inhibitors,research,lifescience,medical robust effects extending as far as 10 years following Enzastaurin research buy discontinuation of treatment.183 In one study of anxious

older adults, benefits of CBT were increased at 1-year follow-up in patients who had been treated for at least 3 months with medications prior to receiving CBT, suggesting that sustained or increasing gains are possible for older adults receiving CBT for anxiety following Inhibitors,research,lifescience,medical an acute course of pharmacotherapy.184 The strategy of sequencing medication with CBT is controversial in the anxiety disorders.185,186 Pharmacotherapy might interfere with the challenging of catastrophic beliefs during psychotherapy, individuals treated with medications may be less motivated to engage in psychotherapy, and psychotherapy in the context of medications may result in state-dependent learning that does not persist after the medication is discontinued.187,188 Because of this, we are currently testing first the strategy of sequenced medication and CBT within a controlled study design. Future directions in treatment development: new targets and one large barrier The preceding sections raise several avenues for novel treatment development. Our findings with cortisol in late-life GAD are summed up as such: elevated cortisol is associated with GAD, is reducible with treatment, and when reduced during treatment is associated with neuropsychological improvements (in memory).

3 The parallels, on multiple levels of analysis, have become sufficiently striking as to suggest that there is a deep connection between neuroplasticity and mood regulation, although

why this should be so remains to be elucidated.13 Stress, especially when it is chronic and uncontrollable, produces a depression-like behavioral profile in animal models14,15 Inhibitors,research,lifescience,medical and is thought to be a trigger for the Cilengitide in vitro development of major depression in genetically vulnerable individuals.16 Chronic stress has numerous effects on plasticity-associated processes throughout the brain in rodent models.3,14,17 In the hippocampus, chronic Inhibitors,research,lifescience,medical stress produces dendritic atrophy, especially in the CA3 region18; prolonged pharmacological elevation of glucocorticoids, the principle adrenal stress hormones, can lead to cell death.19 Severe stress can also inhibit long-term potentiation (LTP)20 and enhance long-term depression in the hippocampus.21 Similar effects are seen in the frontal cortex in rodents: both chronic behavioral stress and

corticosteroid agonists lead to atrophy of the apical dendrites of layer 5 pyramidal cells in the frontal cortex22 and to reduced dendritic spines in the medial prefrontal cortex.23,24 Stress also inhibits some forms of synaptic LTP of synapses Inhibitors,research,lifescience,medical onto prefrontal pyramidal cells.24 Brain plasticity Inhibitors,research,lifescience,medical also occurs at the level of neurogenesis: the production of new neurons, particularly in the dentate gyrus of the hippocampus, and their integration into the functional circuitry. This is another form of neuroplasticity that may contribute to memory formation.25-27 Chronic stress impairs neurogenesis in the dentate gyrus.28,29 These effects of stress and Inhibitors,research,lifescience,medical stress hormones on the substrates and mechanisms of plasticity are, unsurprisingly, paralleled by cognitive impairments after stress in animal models.

Transient mild stress can actually enhance learning and memory; this may represent an adaptive response to threatening situations.30 MTMR9 More extended stress, however, disrupts hippocampus-dependent memory in experimental animals.31 Corticosteroid treatment has similar effects.32,33 What is the relevance to human psychopathology of these effects of stress on plasticity and on mnemonic processes in experimental animals? Neuroimaging and postmortem studies in humans indicate that structural changes are seen in MDD, supporting the parallel between the effects of experimental stress and the pathophysiology of mood disorders. Structural MRI studies have revealed reduced hippocampal volume in individuals with depression,34,35 reminiscent of the experimentally documented effects of chronic or severe stress.

We can thus extrapolate from this that vigilance

for threatening faces is not an exclusive function of anxiety as previously reported (see review paper by Mogg and ZSTK474 mw Bradley 2005). Once again, a possible explanation for why the present study found significance for threat stimuli in sad mood while others have found this primarily in anxious samples (e.g.,Van Honk et al. 2001; Mogg and Bradley 2002; Mogg et al. 2007) can perhaps be due to the exclusive use of verbal stimuli. Valenced verbal stimuli, although highly valuable for the study of attentional bias, may lack Inhibitors,research,lifescience,medical the potency necessary to elicit an externally driven attentional bias, namely for threatening angry faces. For instance, a survey of the referenced articles in the review paper by Mogg and Bradley (2005) reveals that with the exception of one study that utilized Inhibitors,research,lifescience,medical emotional face stimuli (Bradley et al. 1999), all other experiments utilized emotional words. If the suggestion about faces having more strength for threat detection

holds true, this could partially explain the lack of findings for an external threat bias in both sad mood and depressed samples. Second, although highly speculative at this point, it is not entirely convincing that threatening faces are Inhibitors,research,lifescience,medical strictly signals of danger in the environment and thus belong exclusively in the anxiety attentional bias camp. An angry face can possibly be a signal of impending doom and aggression for the anxious observer or a signal of disapproval and rejection for the

sad or depressed observer. Lastly, contrary to our hypothesis, happy mood participants did not pay more attention to positive stimuli. In the Inhibitors,research,lifescience,medical present study, these participants paid less attention to negative stimuli suggesting that perhaps the protective bias can also be defined by what healthy controls do not attend to, namely negative stimuli. Summary and Conclusions The present study investigated attentional interference for both emotional words and emotional faces across a wide range of valences. Overall, the present results Inhibitors,research,lifescience,medical support earlier studies indicating that people in a sad mood show slower reaction times to processing affective. A limitation of our study merits comment. To assess self-processing within an emotional context, Endonuclease it has been recommended that valenced words be restricted to self-referencial stimuli (Fossati et al. 2003). The present study controlled for many aspects of the verbal stimuli (e.g., arousal, word length) but was not exclusively categorized by self-referential words. Overall, the present results support earlier studies indicating that people in a sad mood show slower reaction times to processing affective information (Leppanen 2006), particularly when the stimuli are negatively valenced (Baumeister et al. 2001). We have identified specific verbal and facial emotional cues that lead to interference in attention for those in a sad mood.

As it was expected, SN further enhanced the protection with the APR of 6.7. (Table 4 experiment 4). When DTO was coencapsulated with Rh (Table 4 experiment 5), the APR was 3.9. When DTO was coencapsulated with TS and Rh, (SL-DTO-Rh) the APR was enhanced to 4.9 (Table 4 experiment 6). The highest protection (APR = 15.3) was achieved with the combination of (SL-DTO-TS-Rh) and SN (Table 4 experiment 7). Expressing the relative antidotal potency ratios (RAPR) better indicates the differences

in protection with two antidotal systems (Table 5). Comparing experiment 2 and 3 (RAPR = 2.2) represents the effects of TS coencapsulation with DTO. When comparing experiments 3 and 4 (RAPR = 1.4) or experiments 6 and Inhibitors,research,lifescience,medical 7 (RAPR = 3.1) the enhancement effects reached by SN are represented. The significant enhancement by Rh is expressed when comparing experiments 2 and 5 (RAPR Inhibitors,research,lifescience,medical = 1.8) and experiments 4 and 7 (RAPR = 2.3) confirming earlier studies with other types of encapsulation formulations for Rh [23, 26, 27]. Table 5 Relative

prophylactic antidotal potency ratios (RAPRs) to express enhancing effects by Rh, SN, and coencapsulated TS. Table 6 shows the therapeutic antidotal protection with the (SL-DTO-TS-Rh) combinations with and without SN. At approximately 2 LD50 dose of KCN Inhibitors,research,lifescience,medical (15mg/kg), all the 6 animals survived in each experiment (Table 6 experiments 1, 2, and 3). However, when the KCN

Inhibitors,research,lifescience,medical dose was enhanced (20mg/kg, approximately 3 LD50) the survival rate with (SL-DTO-TS) + SN was 67% (Table 6 experiment 4), while with (SL-DTO-TS) without SN provided a 50% survival rate (Table 6 experiment 6). Selleckchem Cabozantinib However the (SL-DTO-TS-Rh) antidotal system with and without SN also provided a 100% therapeutic protection (Table 6 experiments 5 and 7). Table 6 Therapeutic protection by various CN antidotal combinations. Control: KCN LD50 = 7.8 (4.6–13.1) mg/kg. Inhibitors,research,lifescience,medical 4. Conclusions The present experiments and results are confirming that the approach of utilizing externally administered, encapsulated, metabolizing rhodanese may have broad implications in cyanide antidotal therapy. The application of this approach very has been successfully tested in animal models. In summary, these studies are describing the prophylactic and therapeutic in vivo efficacy of the encapsulated Rh and the new, reactive sulfur donor DTO. Optimization efforts were attempted for the liposomal lipid compositions, Rh-load, and coencapsulation of two sulfur donors (TS and DTO) and Rh to enhance the encapsulation efficiency for the given components. Optimization of the carrier systems is always a major part of these types of research efforts. Considering the high lipophilicity of DTO, for further in vivo applications other introduction routes (e.g., intramuscular) with further formulation optimizations are recommended.

99 An apt summary of these myriad findings would be that stress research and aging research are intersecting: accelerated aging and stress hyperreactivity (as seen in anxiety disorders) are overlapping concepts. Thus, for late-life anxiety disorders, agents that affect aging pathways (such as rapamycin or calorie restriction mime tics) may be among the novel treatments that benefit health and cognition. Unfortunately, despite the wealth of research in the stress, immunology, and aging fields that could be applied to elucidate these connections, no longitudinal

Inhibitors,research,lifescience,medical research, to our knowledge, has been done or is underway to elucidate the long-term consequences of chronic pathological anxiety in late life, their Inhibitors,research,lifescience,medical mechanisms, and/or novel treatments to reverse this “accelerated aging” process. Comorbidity of anxiety with depression in the elderly Depressed individuals at all ages, including older adults, commonly have comorbid anxiety symptoms or disorders. Z-VAD-FMK molecular weight Longitudinally, anxiety symptoms appear to lead to depressive symptoms, more likely than is the case vice versa.100 Anxiety disorders could therefore be a risk factor for late-life Inhibitors,research,lifescience,medical depression as well as a predictor of persistence and relapse, as in young adults.14,101,102-106 Some research disputes this assertion.107 On the whole, though, studies support the conceptualization of anxious depression as a severe, treatment-relevant subtype of depression

throughout Inhibitors,research,lifescience,medical the lifespan. It remains unknown whether anxious depression reflects diagnostic or dimensional phenotypic overlap, a common neurobiological, behavioral, and/or psychological underpinning, or some additional heterogeneity. Anxious depression might be particularly relevant in older adults, in whom it predicts more cognitive decline44 and greater suicide risk108 than nonanxious depression. Treatment Pharmacological

treatments for anxiety disorders do not always have the same benefits or risks across the lifespan. Inhibitors,research,lifescience,medical Additionally, in the case of psychotherapy, treatments typically need to be adapted for older adults.30,109 This section summarizes treatment literature in geriatric anxiety disorders, discusses new directions in treatment development for older adults, and then provides a set of management many guidelines for clinicians. Psychotherapy Cognitive behavioral therapy (CBT) is the mainstay for anxiety disorder treatment. In younger adults, it is a treatment of choice, particularly when exposure-based, for most anxiety disorders (although it is by no means the only effective approach in these cases). It remains unclear whether CBT is superior to other psychotherapy approaches in late-life anxiety disorders; however, this is presently the dominant and most widely available formal psychotherapy for anxiety disorders. CBT might be particularly effective for anxiety disorders in cognitively intact, motivated older adults who are able to learn new skills in CBT and use them effectively.

Isolated pulmonary valve stenosis (PS) makes up 6-9% of all congenital heart defects among children. PS is divided into valvar, subvalvar, supravalvar, according to the anatomically stenotic portion, and valvar PS is known to be the most common type. The type of stenosis may be the deciding point for the method of therapy, surgical or interventional, and its effects.1) PS can be divided into mild,

moderate, and severe according to Inhibitors,research,lifescience,medical the pressure gradient between the systemic pressure and the right ventricle systolic pressure (RVSP): mild to moderate (RVSP ≤ 75% of systemic pressure); severe (RVSP 76-100% of systemic pressure); critical (RVSP > 100%). In the past, these patients were candidates Inhibitors,research,lifescience,medical of surgical valvotomy, but in moderate to severe PS, percutaneous balloon pulmonary valvuloplasty (BPV) has risen as the first treatment option since the first introduction in 1982.2) Since the initial adoption of the procedure, equipment for BPV has improved and the skills of the performers have ameliorated, leading to minimal complications and its usefulness, proven in many previous studies.3-5)

The initial gold standard for diagnosis of PS is by echocardiography. In 2-dimensional (2D) echocardiography there can be evidence of right ventricle (RV) hypertrophy, RV enlargement, or right atrial enlargement. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical Color flow Doppler imaging demonstrates high-velocity turbulent systolic flow through the pulmonary valve.6) Pressure gradients can simultaneously be estimated by continuous wave Doppler.7) Pressure gradients consist of echocardiographic systolic pressure gradient and mean pressure gradient. In case of aortic valve stenosis which is similar obstruction Inhibitors,research,lifescience,medical disease, mean pressure gradient is considered more important for Angiogenesis inhibitor evaluation of disease among those two gradients.8) However, the most accurate diagnosis still remains to be measurement of the pressure gradient through transcatheterization. The purpose of this study is to compare the difference between the echocardiographic data to

the cardiac catheterization data on the diagnosis, treatment, and follow-up in patients Terminal deoxynucleotidyl transferase diagnosed as PS, and to see what parameters should be closely monitored. Methods Subjects A total of 112 patients (Male : Female = 46 : 66) who underwent BPV at Severance Cardiovascular Hospital, between December, 2002 to August, 2012 were retrospectively analyzed. The patients were all under 16 years of age and critical PS patients who underwent BPV were excluded from this study. The age range was between 1 month to 192 months and mean age 38.35 months (± 48.55 months). Patients with concomitant simple observable heart diseases such as atrial septal defect or patent foramen ovale were included, but those with complex heart diseases were excluded.

In patients undergoing cytoreductive surgery together with hyperthermic intraperitoneal chemotherapy, only one previous study which we are aware of assessed the relationship between splenectomy and postoperative neutropenia; no association was found (25). Therefore, we chose to examine the effect of splenectomy on hematologic toxicity after hyperthermic intraperitoneal chemotherapy with cytoreductive surgery, and assess the

use of granulocyte colony stimulating factor. In the patients who Wnt inhibitor underwent Inhibitors,research,lifescience,medical splenectomy, the white cell nadir was higher, and therefore, splenectomy ameliorated the neutropenia attendant to hyperthermic intraperitoneal chemotherapy. This resulted in a significant decrease in the need for recombinant granulocyte colony stimulating factor support using a standard protocol Inhibitors,research,lifescience,medical for its utilization. The platelet nadir was also higher in the splenectomy group, though this did not result in a significant difference in platelet utilization. Since patients who underwent splenectomy in this experience had disease seen grossly on the organs, splenectomy also correlates

Inhibitors,research,lifescience,medical with increased tumor burden. Consequently, it is not surprising that a significantly higher grade hemoglobin toxicity was seen in the splenectomy cohort as they required a more extensive operative intervention. This is consistent with the lower hemoglobin nadir in the splenectomy group, and translated into significantly more red blood cell transfusions in this population. Furthermore, given the increased peritoneal dissemination in splenectomy patients compared to non-splenectomy patients, Inhibitors,research,lifescience,medical and thus the need for more extensive multivisceral resection, it is also not surprising that the splenectomy cohort had, on average, a significantly longer hospital stay. Additionally, while a higher proportion of splenectomy patients Inhibitors,research,lifescience,medical expired, there was not a statistically significant difference

in the mortality between the two groups or in the proportion of patients who expired from cytopenia. Splenectomy is associated with morbidities including Mannose-binding protein-associated serine protease atelectasis, pleural effusion, pancreatic injury, thrombocytosis, subphrenic abscess, and pancreatic pseudocyst formation (26). A feared complication after splenectomy is overwhelming sepsis, which has an overall mortality of 50%, and may occur between 24 days to 65 days after surgery (27). Pneumococcus is the causative organism in over 60% of cases. Our current standard of care involves vaccination with polyvalent pneumococcal vaccine, H. influenzae type b conjugate, and meningococcal polysaccharide vaccine within 2 weeks of splenectomy (28). We routinely administer, and suggest vaccinations for patients undergoing splenectomy. When splenectomy can be anticipated based upon imaging, preoperative vaccination is preferred.

1% (v/v) Tween 20; pH 7.6) containing 5% skim milk. The membranes were

washed in TBST and incubated with guinea pig anti-VAChT (AB1588, Millipore), anti-ChAT (AP144P, Millipore), or anti-CHT (AB5966, Millipore) antibodies overnight at 4°C. Following successive washing with TBST, the membranes were incubated with the appropriate horseradish peroxidase-conjugated secondary antibody. Immunoreactive signals were detected using the SuperSignal West Dura enhanced chemiluminescence system (Pierce, Rockford, IL). To quantify the relative amount of protein expression, blots were Inhibitors,research,lifescience,medical stripped and reprobed with antibodies against GAPDH (H86504M, Meridian Life Science, Memphis, TN) for 1 h followed by a horseradish peroxidase-conjugated secondary antibody for an additional hour. Signal intensities were analyzed using GeneTools software (Syngene, Frederick, MD) and normalized to GAPDH. The relative amount of VAChT, ChAT, and CHT protein in B6eGFPChAT tissue homogenates was expressed as a percent of protein present in B6 control tissue. Mean normalized densitometry values were Inhibitors,research,lifescience,medical analyzed by Student’s Inhibitors,research,lifescience,medical t-test to compare genotypes. Spontaneous activity and indirect calorimetry B6eGFPChAT (N = 8) and B6 (N = 8) mice were learn more placed in comprehensive lab animal monitoring system (CLAMS) metabolic cages (Columbus Instruments, Columbus, OH). These metabolic chambers monitor activity and metabolic performance.

Following entry into the cages, the mice were allowed to acclimatize to the environment for 14–17 h prior to data collection. High-resolution real time activity data along with metabolic measurements collected every 10 min were acquired during the 12 h light cycle Inhibitors,research,lifescience,medical (0700 and 1900 h) and 12 h dark cycle (1900 and 0700 h). The metabolic measurements included the Inhibitors,research,lifescience,medical volume of carbon dioxide produced (VCO2), the volume of oxygen consumed (VO2), the respiration exchange

ratio (RER = VCO2/VO2), and the caloric (heat) value (([(3.815 + 1.232 × RER) × VO2] × 1000)/mouse weight). Sleep analysis was conducted using the Oxymax software (Columbus Instruments, Columbus, OH) as previously described and validated (Pack et al. 2007). The sleep threshold was set to 180 sec of ≤10 activity counts. The data are represented in ~30 min intervals and analyzed using repeated measures two-way enough analysis of variance (ANOVA) or as the mean values over each 12 h period and analyzed using Student’s t-test. Dark/light box Each mouse was placed into an automated activity monitor (Accuscan Instruments, Inc., Columbus, OH) that was separated into an enclosed dark region (20 × 40 cm) and an open light region (20 × 40 cm). The two regions were separated by an opening (10 × 15 cm) where mice were placed facing the dark region and allowed to explore for 10 min between 2000 and 2200 h. Activity (converted from infrared beam breaks to cm) in each of the two regions along with transitions between the regions were measured over the trial duration.