Laurie Renner

Circadian Activity Associated With Spatial Learning and Memory in Aging Rhesus Monkeys

In rodents, spatial learning and memory tests require navigation, whereas in nonhuman primates these tests generally do not involve a navigational component, thus assessing nonhomologous neural systems. To allow closer parallels between rodent and primate studies, we developed a navigational spatial learning and memory task for nonhuman primates and assessed the performance of elderly (19-25 years) female rhesus monkeys (Macaca mulatta). The animals were allowed to navigate in a room containing a series of food ports. After they learned to retrieve food from the ports, a single port was repeatedly baited and the animals were tested until they learned the correct location. The location of the baited port was then changed (shift position). We also determined whether test performance was associated with circadian activity measured with accelerometers. Performance measures included trials to criterion, search strategies, and several indices of circadian activity. Animals learned the task as reflected in their search strategies. Correlations were found between the number of initial or shift trials and circadian activity parameters including day activity, dark:light activity ratio, sleep latency, and wake bouts. Thus, disruptions in circadian rhythms in nonhuman primates are associated with poorer performance on this novel test. These data support the usefulness of this spatial navigational test to assess spatial learning and memory in rhesus monkeys and the importance of circadian activity in performance.

Androgen Supplementation During Aging: Development of a Physiologically Appropriate Protocol

Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21-26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of Ts primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7-12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.Abstract Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained...

Hormone Supplementation During Aging: How Much and When?

Circulating levels of dehydroepiandrosterone, a major adrenal steroid, show a marked age-related decrease in both humans and nonhuman primates. Because this decrease has been implicated in age-related cognitive decline, we administered supplementary dehydroepiandrosterone to perimenopausal rhesus macaques (Macaca mulatta) to test for cognitive benefits. Although recognition memory improved, there was no benefit to spatial working memory. To address the limitations of this study we developed a hormone supplementation regimen in aged male macaques that more accurately replicates the 24-hr androgen profiles of young animals. We hypothesize that this more comprehensive physiological hormone replacement paradigm will enhance cognitive function in the elderly.

Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression

Estradiol supplementation has been shown to enhance cognitive performance in old ovariectomized rhesus macaques (Macaca mulatta). To determine if similar benefits could be achieved in perimenopausal animals using alternative hormonal supplements, we administered dehydroepiandrosterone (DHEA) to old ovary‐intact female rhesus macaques for ∼2.5 months. Using computerized touch screen memory tasks, including delayed response (DR) and delayed matching‐to‐sample (DMS), we observed improved performance with time in all of the animals but failed to detect a significant effect of DHEA. On the other hand, gene expression profiling disclosed a significant correlation between cognitive performance and the expression of several steroidogenic and steroid‐responsive genes. The DR performance was positively correlated with hippocampal expression of AKR1C3 and STAR and negatively correlated with the expression of SDRD5A1. A positive correlation was also found between DMS performance and prefrontal cortical expression of AKR1C3 and a negative correlation with STAR, as well as a negative correlation with the hippocampal expression of HSD11B1 and NR3C1. Taken together, the results suggest that steroidogenic gene regulation within the brain may help to maintain cognitive function during the perimenopausal transition period, despite a decline in sex‐steroid levels in the circulation.

Measuring Cone Density in a Japanese Macaque ( Macaca fuscata ) Model of Age-Related Macular Degeneration with Commercially Available Adaptive Optics

The aim of this study was to assess the feasibility of using a commercially available high-resolution adaptive optics (AO) camera to image the cone mosaic in Japanese macaques (Macaca fuscata) with dominantly inherited drusen. The macaques examined develop drusen closely resembling those seen in humans with age-related macular degeneration (AMD). For each animal, we acquired and processed images from the AO camera, montaged the results into a composite image, applied custom cone-counting software to detect individual cone photoreceptors, and created a cone density map of the macular region. We conclude that flood-illuminated AO provides a promising method of visualizing the cone mosaic in nonhuman primates. Future studies will quantify the longitudinal change in the cone mosaic and its relationship to the severity of drusen in these animals.

Discovery of a CLN7 model of Batten disease in non-human primates

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7−/−). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7−/− macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7−/− macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease.

Androgen supplementation during aging

Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21-26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of Ts primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7-12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.Abstract Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained...