Differences between adult and adolescent male mice in approach/avoidance and expression of hippocampal NPY in response to acute footshock.

Anxiety disorders are the most common neuropsychiatric disorders diagnosed in adolescence and adulthood. Stress can lead to an increase in anxiety-related behaviors, although the consequences of stress in rodents are typically investigated only in adults. The levels of Neuropeptide Y (NPY), a mediator of stress resilience, are reduced in adult patients with Post-Traumatic Stress Disorder. For rodents, footshock is a physical stressor that increases anxiety-like behavior and reduces NPY in adults, however, the effects in adolescents are unknown. Here we used a 30-min unpredictable footshock protocol to investigate the differences in behavior and stress-relevant molecules between adolescent (6 weeks) and adult (3 months) male C57Bl6/J mice. The protocol resulted in fear expression in both ages as observed by enhanced freezing during footshock and elevation in plasma corticosterone and NPY shortly after exposure. However, effects on approach/avoidance behavior were different between the two ages. One week after footshock exposure, adult mice showed reduced open arm time and entries on elevated plus maze (EPM), whereas adolescent mice showed no effect. Footshock mice in both age groups displayed reduced activity levels in EPM and open field. The hypolocomotion did not relate to motor deficits, as there were no differences between footshock and control groups using rotarod. Surprisingly, we found that the adolescent mice had elevated NPY peptide expression in hippocampus, whereas adults had reduced expression one week after footshock exposure. Together, these results demonstrate that stress differentially affects both behavior and the important stress resilience factor NPY in adolescents compared to adults.

Combined Therapeutic Penetrating Keratoplasty and Pars Plana Vitrectomy for the Treatment of Infectious Keratitis Endophthalmitis: Mexican Endophthalmitis Study Group Protocol 4.

PURPOSE: The purpose of this study was to assess the role of combined surgical treatment of therapeutic penetrating keratoplasty and pars plana vitrectomy in the anatomical and functional outcome of infectious keratitis endophthalmitis. METHODS: This study reviewed the medical records of 4 participating centers in the United States and Mexico. This study included patients with a clinical diagnosis of infectious keratitis endophthalmitis who had been treated with an early therapeutic penetrating keratoplasty and pars plana vitrectomy as the main treatment for endophthalmitis. From each medical record, the study retrieved demographic data, relevant medical and drug history, baseline clinical manifestation of endophthalmitis, best-corrected visual acuity, and the need for enucleation/evisceration for the control of the infection or any other reason through the follow-up. RESULTS: The study included 48 patients (50.15 ± 20.6 years). The mean follow-up time was 13 ± 0.5 months. The mean best-corrected visual acuity at baseline was 2.1 ± 0.25 logarithm of the minimum angle of resolution. At month 12 was 2.09 ± 0.61 logarithm of the minimum angle of resolution ( P = 0.9). The overall prevalence of enucleation/evisceration was 8.3% (95% confidence interval: 2.32%-19.98%). The prevalence of a vision of no-light perception was 20.8% (95% confidence interval: 2.32%-19.98%). CONCLUSIONS: Combined surgery for severe cases of infectious keratitis endophthalmitis eradicates the infection in most cases, while significantly improving the overall outcomes.

Overexpression of neuropeptide Y decreases responsiveness to neuropeptide Y.

Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age with high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.

Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons.

GABAergic dysfunction has been implicated in a variety of neurological and psychiatric disorders, including anxiety disorders. Anxiety disorders are the most common type of psychiatric disorder during adolescence. There is a deficiency of GABAergic transmission in anxiety, and enhancement of GABA transmission through pharmacological means reduces anxiety behaviors. GAD67-the enzyme responsible for GABA production-has been linked to anxiety disorders. One class of GABAergic interneurons, Neuropeptide Y (NPY) expressing cells, is abundantly found in brain regions associated with anxiety and fear learning, including prefrontal cortex, hippocampus and amygdala. Additionally, NPY itself has been shown to have anxiolytic effects, and loss of NPY+ interneurons enhances anxiety behaviors. A previous study showed that knockdown of Gad1 from NPY+ cells led to reduced anxiety behaviors in adult mice. However, the role of GABA release from NPY+ interneurons in adolescent anxiety is unclear. Here we used a transgenic mouse that reduces GAD67 in NPY+ cells (NPYGAD1-TG) through Gad1 knockdown and tested for effects on behavior in adolescent mice. Adolescent NPYGAD1-TG mice showed enhanced anxiety-like behavior and sex-dependent changes in locomotor activity. We also found enhancement in two other innate behavioral tasks, nesting construction and social dominance. In contrast, fear learning was unchanged. Because we saw changes in behavioral tasks dependent upon prefrontal cortex and hippocampus, we investigated the extent of GAD67 knockdown in these regions. Immunohistochemistry revealed a 40% decrease in GAD67 in NPY+ cells in prefrontal cortex, indicating a significant but incomplete knockdown of GAD67. In contrast, there was no decrease in GAD67 in NPY+ cells in hippocampus. Consistent with this, there was no change in inhibitory synaptic transmission in hippocampus. Our results show the behavioral impact of cell-specific interneuron dysfunction and suggest that GABA release by NPY+ cells is important for regulating innate prefrontal cortex-dependent behavior in adolescents.