Genetic tuning of intrinsically photosensitive retinal ganglion cell subtype identity to drive visual behavior.

The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a subset of the ∼40 retinal ganglion cell types in the mouse retina and drive a diverse array of light-evoked behaviors from circadian photoentrainment to pupil constriction to contrast sensitivity for visual perception. Central to the ability of ipRGCs to control this diverse array of behaviors is the distinct complement of morphophysiological features and gene expression patterns found in the M1-M6 ipRGC subtypes. However, the genetic regulatory programs that give rise to subtypes of ipRGCs are unknown. Here, we identify the transcription factor Brn3b (Pou4f2) as a key genetic regulator that shapes the unique functions of ipRGC subtypes and their diverse downstream visual behaviors.

An ethologically relevant paradigm to assess defensive response to looming visual contrast stimuli.

In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones > > rods > > > ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.

An ethologically relevant paradigm to assess visual contrast sensitivity in rodents.

In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones ˃> rods ˃>>ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.

Practice Patterns of Pancreatic Surgery Within the Military.

INTRODUCTION: Pancreatic surgery is technically challenging, with mortality rates at high-volume centers ranging from 0% to 5%. An inverse relationship between surgeon volume and perioperative mortality has been reported suggesting that patients benefit from experienced surgeons at high-volume centers. There is little published on the volume of pancreatic surgeries performed in military treatment facilities (MTF) and there is no centralization policy regarding pancreatic surgery. This study evaluates pancreatic procedures at MTFs. We hypothesize that a small group of MTFs perform most pancreatic procedures, including more complex pancreatic surgeries. METHODS: This is a retrospective review of de-identified data from MHS Mart (M2) from 2014 to 2020. The database contains patient data from all Defense Health Agency treatment facilities. Variables collected include number and types of pancreatic procedures performed and patient demographics. The primary endpoint was the number and type of surgery for each MTF. RESULTS: Twenty-six MTFs performed pancreatic surgeries from 2014 to 2020. There was a significant decrease in the number of cases from 2014 to 2020. Nine hospitals performed one surgery over eight years. The most common surgery was a distal pancreatectomy, followed by a pancreaticoduodenectomy. There was a decrease in the number of pancreaticoduodenectomies and distal pancreatectomies performed over this period. CONCLUSIONS: Pancreatic surgery is being performed at few MTFs with a downward trajectory over time. Further studies would be needed to assess the impact on patient care regarding postoperative complications, barriers to timely patient care, and impact on readiness of military surgeons.

Surely you can't B. cereus: Bacillus cereus infection resulting in spontaneous pseudoaneurysm of a nonaccessed arteriovenous graft.

Vascular graft infections are a well-described complication of loop arteriovenous grafts (AVGs) placed for hemodialysis access and are reported to occur in 0.5% to 6.0% of AVGs. The most common microorganisms implicated in these infections are the Staphylococcus species. We present a case of a chronically nonaccessed graft rupture caused by an indolent B. cereus colonization, which is usually a foodborne contaminant. The finding of this organism as the causal agent in an AVG infection warrants further research into the potential emergence of the Bacillus species as a contributing factor in the morbidity and mortality resulting from AVG infection.

All the PNS is a Stage: Transplanted Bone Marrow Cells Play an Immunomodulatory Role in Peripheral Nerve Regeneration.

SUMMARY STATEMENT: Bone marrow cell transplant has proven to be an effective therapeutic approach to treat peripheral nervous system injuries as it not only promoted regeneration and remyelination of the injured nerve but also had a potent effect on neuropathic pain.

Practice patterns of hepatobiliary surgery within the military.

BACKGROUND: The purpose of this study is to evaluate the trends of hepatobiliary surgeries performed at military hospitals and to discuss potential implications on resident training and military readiness. While there is data to suggest centralization of surgical specialty services leads to improved patient outcomes, the military does not currently have a specific centralization policy. Implementation of such a policy could potentially impact resident training and readiness of military surgeons. Even in the absence of such a policy, there may still be a trend toward centralization of more complex surgeries like hepatobiliary surgeries. The present study evaluates the numbers and types of hepatobiliary procedures performed at military hospitals. METHODS: This study is a retrospective review of de-identified data from Military Health System Mart (M2) from 2014 to 2020. The M2 database contains patient data from all Defense Health Agency treatment facilities, encompassing all branches of the United States Military. Variables collected include number and types of hepatobiliary procedures performed and patient demographics. The primary endpoint was the number and type of surgery for each medical facility. Linear regression was used to evaluate significant trends in numbers of surgeries over time. RESULTS: Fifty-five military hospitals performed hepatobiliary surgeries from 2014 to 2020. A total of 1,087 hepatobiliary surgeries were performed during this time; cholecystectomies, percutaneous procedures, and endoscopic procedures were excluded. There was no significant decrease in overall case volume. The most commonly performed hepatobiliary surgery was "unlisted laparoscopic liver procedure." The military training facility with the most hepatobiliary cases was Brooke Army Medical Center. CONCLUSION: The number of hepatobiliary surgeries performed in military hospitals has not significantly decreased over the years 2014-2020, despite a national trend toward centralization. Centralization of hepatobiliary surgeries in the future may impact residency training as well as military medical readiness.

The Retinal Basis of Light Aversion in Neonatal Mice.

Aversive responses to bright light (photoaversion) require signaling from the eye to the brain. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) encode absolute light intensity and are thought to provide the light signals for photoaversion. Consistent with this, neonatal mice exhibit photoaversion before the developmental onset of image vision, and melanopsin deletion abolishes photoaversion in neonates. It is not well understood how the population of ipRGCs, which constitutes multiple physiologically distinct types (denoted M1-M6 in mouse), encodes light stimuli to produce an aversive response. Here, we provide several lines of evidence that M1 ipRGCs that lack the Brn3b transcription factor drive photoaversion in neonatal mice. First, neonatal mice lacking TRPC6 and TRPC7 ion channels failed to turn away from bright light, while two photon Ca2+ imaging of their acutely isolated retinas revealed reduced photosensitivity in M1 ipRGCs, but not other ipRGC types. Second, mice in which all ipRGC types except for Brn3b-negative M1 ipRGCs are ablated exhibited normal photoaversion. Third, pharmacological blockade or genetic knockout of gap junction channels expressed by ipRGCs, which reduces the light sensitivity of M2-M6 ipRGCs in the neonatal retina, had small effects on photoaversion only at the brightest light intensities. Finally, M1s were not strongly depolarized by spontaneous retinal waves, a robust source of activity in the developing retina that depolarizes all other ipRGC types. M1s therefore constitute a separate information channel between the neonatal retina and brain that could ensure behavioral responses to light but not spontaneous retinal waves.SIGNIFICANCE STATEMENT At an early stage of development, before the maturation of photoreceptor input to the retina, neonatal mice exhibit photoaversion. On exposure to bright light, they turn away and emit ultrasonic vocalizations, a cue to their parents to return them to the nest. Neonatal photoaversion is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs), a small percentage of the retinal ganglion cell population that express the photopigment melanopsin and depolarize directly in response to light. This study shows that photoaversion is mediated by a subset of ipRGCs, called M1-ipRGCs. Moreover, M1-ipRGCs have reduced responses to retinal waves, providing a mechanism by which the mouse distinguishes light stimulation from developmental patterns of spontaneous activity.

Melatonin Prevents Non-image-Forming Visual System Alterations Induced by Experimental Glaucoma in Rats.

Glaucoma is a blindness-causing disease that involves selective damage to retinal ganglion cells (RGCs) and their axons. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system functions, such as pupillary light reflex and circadian rhythms. We analyzed the effect of melatonin on the non-image-forming visual system alterations induced by experimental glaucoma. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate into the eye anterior chamber. The non-image-forming visual system was analyzed in terms of (1) melanopsin-expressing RGC number, (2) anterograde transport from the retina to the olivary pretectal nucleus and the suprachiasmatic nuclei, (3) blue- and white light-induced pupillary light reflex, (4) light-induced c-Fos expression in the suprachiasmatic nuclei, (5) daily rhythm of locomotor activity, and (6) mitochondria in melanopsin-expressing RGC cells. Melatonin prevented the effect of experimental glaucoma on melanopsin-expressing RGC number, blue- and white light-induced pupil constriction, retina-olivary pretectal nucleus, and retina- suprachiasmatic nuclei communication, light-induced c-Fos expression in the suprachiasmatic nuclei, and alterations in the locomotor activity daily rhythm. In addition, melatonin prevented the effect of glaucoma on melanopsin-expressing RGC mitochondrial alterations. These results support that melatonin protected the non-image-forming visual system against glaucoma, probably through a mitochondrial protective mechanism.

Diversity of intrinsically photosensitive retinal ganglion cells: circuits and functions.

The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are a relatively recently discovered class of atypical ganglion cell photoreceptor. These ipRGCs are a morphologically and physiologically heterogeneous population that project widely throughout the brain and mediate a wide array of visual functions ranging from photoentrainment of our circadian rhythms, to driving the pupillary light reflex to improve visual function, to modulating our mood, alertness, learning, sleep/wakefulness, regulation of body temperature, and even our visual perception. The presence of melanopsin as a unique molecular signature of ipRGCs has allowed for the development of a vast array of molecular and genetic tools to study ipRGC circuits. Given the emerging complexity of this system, this review will provide an overview of the genetic tools and methods used to study ipRGCs, how these tools have been used to dissect their role in a variety of visual circuits and behaviors in mice, and identify important directions for future study.

An evaluation of bariatric surgery in all military treatment facilities.

BACKGROUND: Multiple bariatric databases have been formed, but there have been no comprehensive assessments of military treatment facilities (MTFs). MTFs have unique patients and coverage policies by Tricare insurance. METHODS: MHS Mart (M2) was used to review the outpatient medical record, AHLTA, from October 2013 to December 2018 for type of bariatric procedure, demographics, military-specific data, comorbidities, and complications, which were identified by ICD code and CPT code, including a robotic modifier. MTFs were classified by volume as high (HV) with > 50 cases annually, moderate (MV) with 25 to 50 cases, and low (LV) with < 25 cases, as well as by the presence of surgical residencies. RESULTS: Patients at MTFs were slightly younger and more female than by other database studies. The Army was the most common branch of service, and dependents of retirees were the most common beneficiary population. MTFs with residencies had slightly older patients and fewer Army patients. HV, MV, and LV MTFs had similar patients except for branch of service. Over time, the proportion of open gastric bypasses increased, biliopancreatic diversions with duodenal switches decreased, and robotic assistance increased 744%. MTFs with residencies performed more procedures than those without residencies, and with the exception of procedures utilizing robotic assistance, procedures were overall similar to those without residencies. HV MTFs performed most of the procedures annually, and their procedures were proportionately similar to MV and LV MTFs, with the exception of HV MTFs having a higher proportion of laparoscopic bypasses and robotic assistance. CONCLUSION: MTFs largely perform similar procedures on similar patients relative to MBSAQIP and NSQIP studies. Robotic assistance increased significantly over time. Except for laparoscopic bypasses and procedures with robotic assistance, HV MTFs performed similar proportions of procedures to MV and LV MTFs. MTFs with residencies performed similar procedures to those without residencies.

Chronobiotic effect of melatonin in experimental optic neuritis.

Optic neuritis (ON) is an inflammatory condition of the optic nerve, which leads to retinal ganglion cell (RGC) loss. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system (NIFVS) functions such as pupillary light reflex (PLR) and circadian rhythms. Melatonin is a chronobiotic agent able to regulate the circadian system. We analyzed the effect of ON on the NIFVS, and the effect of melatonin on the NIFVS alterations induced by ON. For this purpose, optic nerves from male Wistar rats received vehicle or bacterial lipopolysaccharide (LPS), and one group of animals received a subcutaneous pellet of melatonin or a sham procedure. The NIFVS was analyzed in terms of: i) blue light-evoked PLR, ii) the communication between the retina and the suprachiasmatic nuclei (by anterograde transport, and ex vivo magnetic resonance images), iii) locomotor activity rhythm, and iv) Brn3a(+) and melanopsin(+) RGC number (by immunohistochemistry). Experimental ON significantly decreased the blue light-evoked PLR, induced a misconnection between the retina and the suprachiasmatic nuclei, decreased Brn3a(+) RGCs, but not melanopsin(+) RGC number. A bilateral injection of LPS significantly increased the light (but not dark) phase locomotor activity, rhythm periodicity, and time of offset activity. Melatonin prevented the decrease in blue light-evoked PLR, and locomotor activity rhythm alterations induced by ON. These results support that ON provoked alterations of the circadian physiology, and that melatonin could restore the circadian system misalignment.

Profiles After Acute Traumatic Injury: The Non-battle Injury Impact on Readiness at a Single Military Treatment Facility.

INTRODUCTION: Physical profiling is critical to the individual medical readiness of all military service members. This classification system provides detailed information about an individual's functional abilities. Profile information is used in determining whether a service member is medically deployable or non-deployable. Limited research has been conducted on the impact of acute traumatic injuries on duty status and profiles in the non-deployed setting. The purpose of this study was to characterize injured service members presenting to a CONUS MTF emergency department whose acute traumatic injury resulted in a profile. MATERIALS AND METHODS: A retrospective review of patients who presented to the Dwight D. Eisenhower Army Medical Center emergency department with traumatic injuries from January 1, 2019, to December 31, 2019, was performed. Patients were identified by searching electronic encounter records for trauma-specific ICD-10 codes. Returned patient records were then reviewed for active duty status, branch, age, gender, rank, mechanism, protective equipment, substance use, procedures, and disposition. Profiles of soldiers were reviewed for indication and duration. Patients with profiles were compared to those without profiles. Correlation with age was determined by t-test, correlation with profile length was determined by ANOVA, and correlation with the remaining categorical variables was determined with chi-squared analysis. RESULTS: Eight hundred and thirty-two service members were reviewed. One hundred and eight (13%) soldiers had a profile. Patients were 23.2% female with no difference between the two groups. Patients were an average of 28.7 years old. The most common mechanisms were physical training (PT) (33.1%) and falls (12.9%). Physical training and motor vehicle collisions were more common in the profile group. Combatives and crush injuries of the hand were less common in the profile group. Major procedures were more common in the profile group, and minor procedures were less common. Admissions, quarters, immediate referrals, and release without limitations were more common in the profile group. The mean duration of profiles was 48.9 days, and 7.4% were permanent. CONCLUSIONS: Non-battle injuries in the garrison setting are a significant threat to readiness. This analysis of acute traumatic injuries suggests that mechanism of injury was similar to previous reports with PT and falls being most common. Interventions should be targeted at PT and motor vehicle collisions as these were more common in the profile group. This series is also similar to previous reports that extremity injuries are the most common cause of profiles. However, TBIs were more common in our analysis. Further research that encompasses all garrison MTF acute traumatic injuries is needed to define the true impact on readiness and guide development of injury prevention strategies.

Efectos del tratamiento antioxidante en la activación del eje hipotálamo-hipófiso-adrenal inducida por el consumo de dietas ricas en sacarosa / Effects of antioxidant treatment on the activation of the hipotalamo-hipofiso-adrenal axis induced by the consumption of sucrose rich diets

Introducción: dados los efectos pleiotrópicos de los glucocorticoides (GCs) sobre el metabolismo, los niveles excesivos y sostenidos de GCs circulantes tienen efectos deletéreos e incrementan la morbilidad y mortalidad cardiovascular. Objetivos: estudiar el efecto de la terapia antioxidante (con ácido lipoico o melatonina) sobre la hiperactivación del eje hipotálamo-hipófiso-adrenal (HHA) en animales alimentados con dieta rica en sacarosa (DRS). Materiales y métodos: se evaluó la actividad del eje HHA y se determinaron parámetros hormonales, de estrés oxidativo y de inflamación en la adenohipófisis de animales tratados con DRS durante tres semanas. Resultados: los animales del grupo DRS mostraron mayores niveles circulantes de hormona adrenocorticotropa (ACTH, por sus siglas en inglés) y corticosterona. En paralelo se detectó un aumento en la expresión del polipéptido precursor (proopiomelanocortina, POMC) y de ACTH en la adenohipófisis, donde también se observó un aumento de lipoperóxidos y proteínas nitradas en tirosina (daño oxidativo), un mayor número de macrófagos tisulares y un incremento en la producción de IL-1beta. El tratamiento antioxidante previno los cambios en estos parámetros. En particular la melatonina también normalizó la actividad del eje HHA y la expresión hipofisaria de POMC. Conclusiones: la sobrecarga metabólica inducida por la administración de DRS genera daño oxidativo e inflamación en la adenohipófisis. La activación de los macrófagos tisulares producida en consecuencia podría impactar sobre los corticotropos hipofisarios e inducir su hiperfunción. La melatonina podría utilizarse como herramienta terapéutica para normalizar la actividad del eje HHA en modelos de obesidad por dieta.

Introduction: given the pleiotropic effects of glucocorticoids (GCs) on metabolism, excessive and sustained levels of circulating GCs, have deleterious effects and increase cardiovascular morbidity and mortality. Objectives: to study the effect of antioxidant therapy on hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis in animals fed a sucrose-rich diet (SRD). Materials and methods: the activity of the HPA axis was evaluated and hormonal, oxidative stress and inflammation parameters were determined in the adenohypophysis of animals treated with SRD for trhee weeks. Results: animals from the SRD group showed higher circulating levels of adrenocorticotropic hormone (ACTH) and corticosterone. In parallel, an increase in the expression of the polypeptide precursors, POMC and ACTH were detected in the adenohypophysis. We also observed an increase in lipoperoxides and proteins nitrated in tyrosine (oxidative damage), a greater number of tissue macrophages and an increase in the production of IL-1beta. Antioxidant treatment prevented all these changes. In particular, melatonin also normalized the activity of the HPA axis and pituitary expression of POMC. Conclusions: the metabolic overload induced by the administration of SRD generates oxidative damage and inflammation in the adenohypophysis. Activation of tissue macrophages could affect, in turn, pituitary corticotrophs inducing their activation. Melatonin could be used as a therapeutic tool to normalize the activity of the HPA axis in diet obesity models.

An Analysis of Burnout among Military General Surgery Residents.

OBJECTIVES: Resident burnout is an increasing issue in graduate medical education programs. Military graduate medical education is unique in numerous ways and may have different rates of burnout as well as different causes. This study aims to assess resident burnout rates and contributing factors among military general surgery residents. DESIGN, SETTING, AND PARTICIPANTS: Using Department of Defense approved software, an anonymous survey was created and distributed to all general surgery residents (n = 180) in 6 US medical centers where there are general surgery residency programs. The survey contained an Abbreviated Maslach Burnout Index questionnaire, multiple choice questions including several military-specific questions, and 2 open ended questions. Rates of burnout and potential risk factors associated with burnout were analyzed. RESULTS: After the collection period, 92 of 180 (51%) residents completed all Abbreviated Maslach Burnout Index questions, demographics, and military specific questions with an opportunity for written comments. Notable demographic findings of the respondents were that 64% were male, 65% were married or engaged, 40% had children, and 69% had no student loan debt. Overall, there was a 66% rate of burnout in any tertile. Variables found to be significant for overall burnout included the likelihood the resident plans to stay beyond their active duty service obligation and the perceived level of autonomy. Of the written responses, the most commonly cited contributing factor was the work burden from nonclinical and/or administrative tasks while the most common protective factor was resident camaraderie. CONCLUSIONS: Overall, burnout rates are similar among military general surgery residents compared to published reports of civilians. The close association with resident burnout and anticipation of early withdrawal from military service demonstrates this topic is potentially important to retention of the military medical force. The topics of increased resident autonomy, decreased non-clinical duties, and efforts to increase resident camaraderie should be more closely evaluated.

Biloma Secondary to Percutaneous Liver Biopsy Case Report.

Biloma and biliary leak after percutaneous liver biopsy (PLB) are rare. Previous cases are largely in the setting of transplant, oncology, and cirrhotic patients. Patients can be asymptomatic, peritoneal, or present with obstructive symptoms, including bilirubinemia. A 55-year-old male referred for transaminitis attributed to nonalcoholic fatty liver disease (NAFLD) underwent an ultrasound- (US-) guided PLB. He returned the same day with abdominal pain, normal vitals, a nontender abdomen, and a leukocytosis. He was found to have a subcapsular fluid collection attributed to a hematoma. He underwent observation and was discharged. He presented 4 days later with fever, tachycardia, leukocytosis, and bilirubinemia. CT demonstrated growth of the subcapsular fluid collection. Percutaneous drainage revealed bilious fluid. He was transferred for endoscopic retrograde cholangiopancreatography (ERCP). A right biliary branch was stented, and he was discharged the following day with antibiotics. US should be utilized for percutaneous biopsies to avoid biliary complications. Typical presentations of biliary complications include abdominal pain and biliary obstruction. The differential diagnosis for perihepatic and subcapsular fluid collections after PLB should include bile. ERCP should be offered for the treatment of larger or symptomatic collections.

Melatonin protects the retina from experimental nonexudative age-related macular degeneration in mice.

Nonexudative age-related macular degeneration (NE-AMD) represents the leading cause of blindness in the elderly. Currently, there are no available treatments for NE-AMD. We have developed a NE-AMD model induced by superior cervical ganglionectomy (SCGx) in C57BL/6J mice, which reproduces the disease hallmarks. Several lines of evidence strongly support the involvement of oxidative stress in NE-AMD-induced retinal pigment epithelium (RPE) and outer retina damage. Melatonin is a proven and safe antioxidant. Our aim was analysing the effect of melatonin in the RPE/outer retina damage within experimental NE-AMD. The treatment with melatonin starting 48 h after SCGx, which had no effect on the ubiquitous choriocapillaris widening, protected visual functions and avoided Bruch´s membrane thickening, RPE melanin content, melanosome number loss, retinoid isomerohydrolase (RPE65)-immunoreactivity decrease, and RPE and hotoreceptor ultrastructural damage induced within experimental NE-AMD exclusively located at the central temporal (but not nasal) region. Melatonin also prevented the increase in outer retina/RPE oxidative stress markers and a decrease in mitochondrial mass at 6 weeks post-SCGx. Moreover, when the treatment with melatonin started at 4 weeks post-SCGx, it restored visual functions and reversed the decrease in RPE melanin content and RPE65-immunoreactivity. These findings suggest that melatonin could become a promising safe therapeutic strategy for NE-AMD.

The "Use It or Lose It" Dogma in the Retina: Visual Stimulation Promotes Protection Against Retinal Ischemia.

Enriched environment (EE) protects the retina from adult rats against ischemia/reperfusion (I/R) injury; however, how the components of EE contribute to the recovery after retinal ischemic damage remains unclear. We analyzed the contribution of social, cognitive, and visual stimulation on functional and histological alterations induced by I/R. Male Wistar rats were submitted to unilateral ischemia by increasing intraocular pressure to 120 mmHg for 40 min. After ischemia, animals were housed in the following conditions: standard environment (SE), enriched environment (EE), novelty environment (NE), standard social environment (SoE), standard visual environment (SVE), or visual environment (VE). In another set of experiments, rats were submitted to bilateral ischemia and housed in SE or EE. At 2 weeks post-ischemia, rats were subjected to electroretinography and histological analysis. EE (but not SoE or NE) afforded functional and histological protection against unilateral ischemia. EE did not induce protection in animals submitted to bilateral ischemia. VE protected retinal function and histology and increased retinal BDNF levels, while a TrkB receptor antagonist prevented the protective effect of VE against I/R damage. In animals submitted to unilateral ischemia, EE and VE induced an increase in c-fos immunoreactivity in the ipsi and contralateral superior colliculus, whereas in animals submitted to bilateral ischemia, no changes in c-fos-immunoreactivity were observed in either superior colliculus from EE-housed animals. These results support that visual stimulation could be a potent stimulus for driving retinal protection in adult rats through a BDNF/TrkB-dependent mechanism, likely involving the superior colliculus.

Enriched environment provides neuroprotection against experimental glaucoma.

Glaucoma is one of the most frequent causes of visual impairment worldwide, and involves selective damage to retinal ganglion cells (RGCs) and their axons. We analyzed the effect of enriched environment (EE) housing on the optic nerve, and retinal alterations in an induced model of ocular hypertension. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate (CS) into the eye anterior chamber for 10 weeks and housed in standard environment or EE. EE housing prevented the effect of experimental glaucoma on visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament-immunoreactivity, axon number, microglial/macrophage reactivity (ionized calcium binding adaptor molecule 1-immunoreactivity), and astrocytosis (glial fibrillary acidic protein-immunostaining), as well as oligodendrocytes alterations (luxol fast blue staining, and myelin basic protein-immunoreactivity) in the proximal portion of the optic nerve. Moreover EE prevented the increase in ionized calcium binding adaptor molecule-1 levels, and RGC loss (Brn3a-immunoreactivity) in the retina from hypertensive eyes. EE increased retinal brain-derived neurotrophic factor levels. When EE housing started after 6 weeks of ocular hypertension, a preservation of visual evoked potentials amplitude, axon, and Brn3a(+) RGC number was observed. Taken together, these results suggest that EE preserved visual functions, reduced optic nerve axoglial alterations, and protected RGCs against glaucomatous damage.