Magnetic Resonance Imaging-Guided Frameless Stereotactic Injections of the Bilateral Cerebellar Dentate Nuclei in Nonhuman Primates: Technical Note.

BACKGROUND AND OBJECTIVES: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. METHODS: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. RESULTS: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). CONCLUSION: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.

Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2-infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163+ MRC1- inflammatory macrophages in BAL and expression of Siglec-1 on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. Using an intervention targeting both IFN-α and IFN-ß pathways, this study shows that, whereas early IFN-I restrains SARS-CoV-2 replication, uncontrolled IFN-I signaling critically contributes to SARS-CoV-2 inflammation and pathogenesis in the moderate disease model of RMs.

Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-ß pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.

Evolution in Parental Leave Policies: Plastic Surgery and Obstetrics/Gynecology Lead the Way.

BACKGROUND: Forty percent of physicians anticipate becoming parents during residency. This often occurs in the absence of clear parental leave and breastfeeding policies, which may adversely impact parental and child health or jeopardize residents' board eligibility, fellowship, and job prospects. This study reports on the current status of parental leave and breastfeeding policies across all specialties. METHODS: Twenty-six specialties recognized by the Accreditation Council for Graduate Medical Education were included. The maximum leave allowed in 2020 and breastfeeding accommodations during board examinations were collected for each specialty. Change in leave since 2006, 2018, and breastfeeding accommodations were analyzed by specialty. RESULTS: In 2020, the median time allowed for parental leave without the extension of training was 5 weeks, and there was no significant difference between 2006, 2018, and 2020 ( p = 0.58). In 2020, plastic surgery and obstetrics/gynecology provided the longest parental leave at 12 weeks. Surgical specialties provided 1 additional week of leave as compared to medical specialties after adjusting for year ( p = 0.02). Twenty-one specialties (81 percent) allowed additional time for lactation during board examinations; however, only seven (27 percent) guaranteed a private location to pump. CONCLUSIONS: There has been little improvement in parental leave allowances since 2006, and the current median, 5 weeks, falls short of guidelines recommending 6 to 12 weeks following the birth of a child. Starting in July of 2021, the Accreditation Council for Graduate Medical Education will require medical boards to provide a minimum of 6 weeks of leave. Ongoing improvement in culture and policy are needed to support residents and their families.

Parenting in Plastic Surgery Residency.

BACKGROUND: In 1994, Mackinnon advocated that plastic surgery residents should have accessible child care to promote a productive return to work. Decades later, lack of adequate child care remains a dilemma for trainees. The authors' survey aims to evaluate childrearing during plastic surgery training. METHODS: An anonymous, voluntary survey was sent to plastic surgery residents. It evaluated demographics, childcare accommodations, and attitudes/issues surrounding childrearing during residency. RESULTS: There were 32 respondents: 66 percent women and 34 percent men. Seventy-five percent were married, and 38 percent were parents. Seventy-five percent of male parents compared to 12 percent of female parents reported that their spouse was the primary childcare source. One hundred percent of respondents with children reported that child care creates a financial burden. Three percent of respondents felt their institution provided services to arrange adequate child care. Sixty-three percent of residents felt their program did not allow flexibility to accommodate childcare needs. Female residents missed work twice as often and were twice as likely to require a co-resident to cover clinical duties because of childcare difficulties when compared to male residents (p = 0.296 and p = 0.145). Sixty-seven percent of women agreed with the statement, "If you had to pick a residency program today, the availability of on-site child care would influence your decision," compared to only 9 percent of men (p = 0.002). CONCLUSIONS: Training institutions are not meeting the childcare needs of plastic surgery trainees. If the specialty wishes to recruit and retain the top applicants, it must improve the childcare accommodations for residents. All institutions with plastic surgery residency programs should provide affordable, accessible child care that accommodates the 24-hour natures of both patient care and parenthood.

A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection.

SARS-CoV-2 vaccines should induce broadly cross-reactive humoral and T cell responses to protect against emerging variants of concern (VOCs). Here, we inactivated the furin cleavage site (FCS) of spike expressed by a modified vaccinia Ankara (MVA) virus vaccine (MVA/SdFCS) and found that FCS inactivation markedly increased spike binding to human ACE2. After vaccination of mice, the MVA/SdFCS vaccine induced eightfold higher neutralizing antibodies compared with MVA/S, which expressed spike without FCS inactivation, and protected against the Beta variant. We next added nucleocapsid to the MVA/SdFCS vaccine (MVA/SdFCS-N) and tested its immunogenicity and efficacy via intramuscular (IM), buccal (BU), or sublingual (SL) routes in rhesus macaques. IM vaccination induced spike-specific IgG in serum and mucosae (nose, throat, lung, and rectum) that neutralized the homologous (WA-1/2020) and heterologous VOCs, including Delta, with minimal loss (<2-fold) of activity. IM vaccination also induced both spike- and nucleocapsid-specific CD4 and CD8 T cell responses in the blood. In contrast, the SL and BU vaccinations induced less spike-specific IgG in secretions and lower levels of polyfunctional IgG in serum compared with IM vaccination. After challenge with the SARS-CoV-2 Delta variant, the IM route induced robust protection, the BU route induced moderate protection, and the SL route induced no protection. Vaccine-induced neutralizing and non-neutralizing antibody effector functions positively correlated with protection, but only the effector functions correlated with early protection. Thus, IM vaccination with MVA/SdFCS-N vaccine elicited cross-reactive antibody and T cell responses, protecting against heterologous SARS-CoV-2 VOC more effectively than other routes of vaccination.

Dorsogluteal intramuscular injection depth needed to reach muscle tissue according to body mass index and gender: A systematic review.

AIMS AND OBJECTIVE(S): The objective of this systematic review was to determine the needle length required to reach the dorsogluteal muscle based on body mass index and sex. Our aim was to provide evidence-based recommendations to current intramuscular injection guidelines from the result(s) of this review. BACKGROUND: Studies worldwide are documenting reduced medication effectiveness due to improperly placed dorsogluteal intramuscular injections because of incorrect needle length, wrong site selection and/or obesity. Current intramuscular injection guidelines lack specific instructions according to weight or sex. While there are similar concerns with other injectable sites, this review focuses solely on adult dorsogluteal intramuscular injections. DESIGN: A systematic review of relevant literature of dorsogluteal intramuscular injections based on body mass index and sex. METHODS: This systematic review was reported using the PRISMA checklist 2020. The review protocol was registered with Center for Open Science (OSF). We analysed 1,412 articles from nine databases. We compared twelve studies that utilised computerised tomography or ultrasonography using The Johns Hopkins Evidence-Based Practice Model and Guidelines. RESULTS: A significant number of dorsogluteal intramuscular injections are administered into subcutaneous tissue rather than muscle because needles are too short for populations with body mass indexes over 25, especially women. Poor landmarking often results in improperly placed injections. CONCLUSIONS: To prevent administering a dorsogluteal intramuscular injection into subcutaneous tissue, women with a BMI of 25 and over require needles longer than 38 mm (1.5 inches). Men have less subcutaneous tissue in the dorsogluteal area and only require longer needles if BMI is 35 and over. If skin-to-muscle depth is questionable in either sex, an ultrasound-guided intramuscular injection is warranted for accurate dorsogluteal placement. Landmarking and needle length are key to appropriately placed IM injections. RELEVANCE TO CLINICAL PRACTICE: Dorsogluteal injections are often injected into subcutaneous tissue rather than muscle because needles are not long enough to reach muscle, especially in women. Critical elements that determine placement of intramuscular injections into muscle versus subcutaneous tissue are sex, BMI, needle length and landmarking. Medications delivered into subcutaneous tissue may have reduced bioavailability.

The Efficacy of Pectoralis Nerve Blockade in Breast Reductions: A Prospective Randomized Trial.

BACKGROUND: Pectoralis nerve (Pecs) blocks have been shown to reduce perioperative opioid consumption in patients undergoing mastectomies, but the effectiveness of these blocks in breast reductions has not been established. This trial aims to evaluate the efficacy of Pecs blocks (I and II) on perioperative pain management in patients undergoing breast reductions. METHODS: Thirty-six patients were enrolled in the randomized controlled trial divided into 2 groups. The treatment group (n = 16) received general anesthesia plus postinduction ultrasound-guided Pecs blocks. The control group (n = 20) received general anesthesia alone. The primary outcomes measured were perioperative narcotic requirements, need for postoperative antiemetics, pain scores, and length of time in the operating room (OR). We measured patient and procedural risk factors including pedicle/skin excision patterns, concurrent liposuction, weight of resection, and additional local anesthesia. Risk factors as well as outcomes were analyzed using Fischer exact and t tests. RESULTS: No statistically significant difference was shown between the group receiving the Pecs blocks and the control with regard to narcotic requirements, pain scores, and need for antiemetics. Patients undergoing Pecs blocks had a significantly higher OR time before incision (P = 0.0073). Patient and procedural risk factors were well balanced (P > 0.41). CONCLUSIONS: Pectoralis nerve blocks may be a valuable component of a multimodality pain regimen; however, when performed as a solitary adjunct, they do not seem to decrease perioperative narcotic requirements, pain scores, or the need for antiemetic medication in patients undergoing breast reductions. In addition, postinduction Pecs blocks significantly increase OR times.

Mineralized Trichobezoars in a Rhesus Macaque (Macaca mulatta).

A five-year-old female rhesus macaque (Macaca mulatta) presented with a thin body condition and multiple palpable mid-abdominal masses. Mineralized cecal trichobezoars were removed surgically. Thirteen months later, similar masses recurred and were confirmed with radiographs. This is the first case report of a mineralized cecal trichobezoar in a rhesus macaque.

Suspected Anaphylactic Reaction to Ketamine in 3 Yucatan Swine (Sus scrofa).

This case series describes the clinical courses of 3 juvenile Yucatan miniature swine (Sus scrofa) that experienced a suspected anaphylactic reaction to ketamine hydrochloride during premedication for protocol-related surgery. All 3 swine rapidly developed diffuse erythema shortly after injection with ketamine-containing drug combinations. Clinical signs ranged from tachycardia and erythema alone to tachycardia and erythema followed by respiratory and cardiac arrest. Ketamine was considered the most likely cause of these reactions because it was the only agent in the premedication sedation combination that was used in all 3 swine. Subsequent intradermal skin testing confirmed this suspicion. With supportive care measures and standard medical interventions for anaphylaxis, all 3 animals recovered well and went on to be successful experimental subjects when an alternative anesthetic regimen that did not contain ketamine was used. To our knowledge, this report is the first description of a suspected adverse ketamine reaction of this type in swine despite the widespread use of the drug in this species. Ketamine anaphylaxis is rare in people, but the few cases described presented with symptoms similar to the clinical signs seen in the pigs in this report. In addition to highlighting a potential adverse drug reaction to ketamine in swine, this case series demonstrates the value of emergency preparedness for even the most routine of procedures.

Environmental drivers of paralytic shellfish toxin producing Alexandrium catenella blooms in a fjord system of northern Southeast Alaska.

Paralytic shellfish poisoning (PSP) is a persistent problem that threatens human health and the availability of shellfish resources in Alaska. Regular outbreaks of marine dinoflagellates in the genus Alexandrium produce paralytic shellfish toxins (PSTs) that make shellfish consumption unsafe, and impose economic hardships on Alaska's shellfish industry. Phytoplankton and environmental monitoring spanning 2008-2016, and a pilot benthic cyst survey in 2016, were focused in the Juneau region of Southeast Alaska to investigate Alexandrium catenella distributions and conditions favorable to bloom development. Overwintering Alexandrium cysts were found in near-shore sediments throughout the study region. Alexandrium catenella cells were present in the water column across a range of sea surface temperatures (7-15 °C) and surface salinities (S = 4-30); however, an optimal temperature/salinity window (10-13 °C, 18-23) supported highest cell concentrations. Measurable levels of PSTs were associated with lower concentrations (100 cells L-1) of A. catenella, indicating high cell densities may not be required for shellfish toxicity to occur. Several interacting local factors were identified to support A. catenella blooms: 1) sea surface temperatures ≥7 °C; 2) increasing air temperature; 3) low to moderate freshwater discharge; and 4) several consecutive days of dry and calm weather. In combination, these bloom favorable conditions coincide with toxic bloom events during May and June in northern Southeast Alaska. These findings highlight how integrated environmental and phytoplankton monitoring can be used to enhance early warning capacity of toxic bloom events, providing more informed guidance to shellfish harvesters and resource managers in Alaska.

Dimensions of national culture associated with different trajectories of male and female mean body mass index in countries over 25 years.

Cultural determinants of obesity prevalence have been little studied but could explain significant variations in body mass index (BMI) trajectories among countries. This ecological study quantified longitudinal associations between six dimensions of national culture and mean population BMI over 25 years. National mean male and female BMI data 1990 to 2014 provided dependent variables. National dimensions of culture (from the Hofstede database for up to 87 countries) were independent variables: Individualism, Uncertainty avoidance, Indulgence, Long-term orientation, Power distance, and Masculinity. Analyses used mixed models for repeated measures for each dimension of national culture with male and female adult BMI trajectories, controlling for confounders. A higher mean BMI was significantly associated with higher Individualism, Uncertainty avoidance, Indulgence, and Masculine orientation and with lower Power distance (males only) and lower Long-term orientation (males only). Overall, the national cultural dimensions explained 62.4% (males) and 53.5% (females) of the variance in mean BMI among countries. National cultural characteristics, especially Individualism and Uncertainty avoidance, are strongly related to obesity prevalence, explaining over half of the variance among countries. More research and theory development is needed to understand the pathways for these associations so that cultural contexts can be better accounted for in policies, social marketing messages, and community-based actions for obesity prevention.

The obesity transition: stages of the global epidemic.

The global prevalence of obesity has increased substantially over the past 40 years, from less than 1% in 1975, to 6-8% in 2016, among girls and boys, and from 3% to 11% among men and from 6% to 15% among women over the same time period. Our aim was to consolidate the evidence on the epidemiology of obesity into a conceptual model of the so-called obesity transition. We used illustrative examples from the 30 most populous countries, representing 77·5% of the world's population to propose a four stage model. Stage 1 of the obesity transition is characterised by a higher prevalence of obesity in women than in men, in those with higher socioeconomic status than in those with lower socioeconomic status, and in adults than in children. Many countries in south Asia and sub-Saharan Africa are presently in this stage. In countries in stage 2 of the transition, there has been a large increase in the prevalence among adults, a smaller increase among children, and a narrowing of the gap between sexes and in socioeconomic differences among women. Many Latin American and Middle Eastern countries are presently at this stage. High-income east Asian countries are also at this stage, albeit with a much lower prevalence of obesity. In stage 3 of the transition, the prevalence of obesity among those with lower socioeconomic status surpasses that of those with higher socioeconomic status, and plateaus in prevalence can be observed in women with high socioeconomic status and in children. Most European countries are presently at this stage. There are too few signs of countries entering into the proposed fourth stage of the transition, during which obesity prevalence declines, to establish demographic patterns. This conceptual model is intended to provide guidance to researchers and policy makers in identifying the current stage of the obesity transition in a population, anticipating subpopulations that will develop obesity in the future, and enacting proactive measures to attenuate the transition, taking into consideration local contextual factors.

Effectiveness of Rapid Cooling as a Method of Euthanasia for Young Zebrafish (Danio rerio).

Despite increased use of zebrafish (Danio rerio) in biomedical research, consistent information regarding appropriate euthanasia methods, particularly for embryos, is sparse. Current literature indicates that rapid cooling is an effective method of euthanasia for adult zebrafish, yet consistent guidelines regarding zebrafish younger than 6 mo are unavailable. This study was performed to distinguish the age at which rapid cooling is an effective method of euthanasia for zebrafish and the exposure times necessary to reliably euthanize zebrafish using this method. Zebrafish at 3, 4, 7, 14, 16, 19, 21, 28, 60, and 90 d postfertilization (dpf) were placed into an ice water bath for 5, 10, 30, 45, or 60 min (n = 12 to 40 per group). In addition, zebrafish were placed in ice water for 12 h (age ≤14 dpf) or 30 s (age ≥14 dpf). After rapid cooling, fish were transferred to a recovery tank and the number of fish alive at 1, 4, and 12-24 h after removal from ice water was documented. Euthanasia was defined as a failure when evidence of recovery was observed at any point after removal from ice water. Results showed that younger fish required prolonged exposure to rapid cooling for effective euthanasia, with the required exposure time decreasing as fish age. Although younger fish required long exposure times, animals became immobilized immediately upon exposure to the cold water, and behavioral indicators of pain or distress rarely occurred. We conclude that zebrafish 14 dpf and younger require as long as 12 h, those 16 to 28 dpf of age require 5 min, and those older than 28 dpf require 30 s minimal exposure to rapid cooling for reliable euthanasia.

LESSONS FROM A RETROSPECTIVE ANALYSIS OF A 5-YR PERIOD OF PRESHIPMENT TESTING AT SAN DIEGO ZOO: A RISK-BASED APPROACH TO PRESHIPMENT TESTING MAY BENEFIT ANIMAL WELFARE.

The preshipment examination, with associated transmissible disease testing, has become standard practice in the movement of animals between zoos. An alternative disease risk-based approach, based on a comprehensive surveillance program including necropsy and preventive medicine examination testing and data, has been in practice since 2006 between the San Diego Zoo and San Diego Zoo Safari Park. A retrospective analysis, evaluating comprehensive necropsy data and preshipment testing over a 5-yr study period, was performed to determine the viability of this model for use with sending animals to other institutions. Animals (607 birds, 704 reptiles and amphibians, and 341 mammals) were shipped to 116 Association of Zoos and Aquariums (AZA)-accredited and 29 non-AZA-accredited institutions. The evaluation showed no evidence of the specific transmissible diseases tested for during the preshipment exam being present within the San Diego Zoo collection. We suggest that a risk-based animal and institution-specific approach to transmissible disease preshipment testing is more cost effective and is in the better interest of animal welfare than the current industry standard of dogmatic preshipment testing.

LESSONS FROM A RETROSPECTIVE ANALYSIS OF A 5-YR PERIOD OF QUARANTINE AT SAN DIEGO ZOO: A RISK-BASED APPROACH TO QUARANTINE ISOLATION AND TESTING MAY BENEFIT ANIMAL WELFARE.

Quarantine is designed primarily to prevent the introduction of transmissible diseases to zoological collections. Improvements in preventive medicine, disease eradication, and comprehensive pathology programs call into question current industry quarantine standards. Disease risk analysis was used at the San Diego Zoo (SDZ) and the SDZ Safari Park to eliminate quarantine isolation and transmissible disease testing for animals transferred between the two institutions. To determine if a risk-based approach might be valid between other institutions and SDZ, we reviewed quarantine data for animals arriving at SDZ from 81 Association of Zoos and Aquariums (AZA)-accredited and 124 other sources (e.g., non-AZA-accredited institutions, private breeders, private dealers, governmental bodies) over a 5-yr period (2009-2013). No mammal or herptile failed quarantine due to transmissible diseases of concern. Approximately 2.5% of incoming birds failed quarantine due to transmissible disease; however, all 14 failed individuals were obtained from three nonaccredited sources (private breeders, confiscation). The results of our study suggest that a risk-based approach could be used to minimize or eliminate quarantine for the transfer of animals from institutions with comprehensive disease surveillance programs and/or preshipment testing practices. Quarantine isolation with testing remains an essential defense against introducing transmissible diseases of concern when there is a lack of health knowledge about the animals being received.

Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice.

Unregulated production of reactive oxygen species (ROS) is a marker of cellular and organismal aging linked to cognitive decline in humans and rodents. The sources of elevated ROS contributing to cognitive decline are unknown. Because NADPH oxidase (Nox) inhibition may prevent memory decline with age, we hypothesized that Nox and not mitochondrial sources of synaptic ROS production are linked to individual variance in cognitive performance in aged mice. Young (8 months) and aged (26 months) mice were tested in the novel object recognition task (NORT). Mitochondrial and Nox ROS production was assayed in isolated synaptosomes using spin trapping electron paramagnetic resonance (EPR) spectroscopy. Aged mice exhibited variance in NORT performance, with some performing similar to young mice while others exhibited poorer short-term memory. EPR studies indicated that Nox rather than mitochondria was the major ROS source at the synapse, and Nox-induced but not mitochondrial-induced ROS levels correlated with NORT performance in aged mice. Our findings support the hypothesis that variance in Nox-specific synaptic ROS production may predict short-term memory deficits with age.

Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain.

Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

Age-associated improvements in cross-modal prepulse inhibition in mice.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe preattentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.