3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats.

Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17alpha-diol (3alpha-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3alpha-diol levels. Chronic, long-term (1-4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3alpha-diol, respectively, could reverse age-associated decline in performance. 3alpha-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3alpha-diol production and 3alpha-diol administration reinstates cognitive and affective performance of aged male rats.

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats.

Androgen levels decline with aging. Some androgens may exert anti-anxiety and cognitive-enhancing effects; however, determining which androgens have anxiolytic-like and/or mnemonic effects is of interest given the different mechanisms that may underlie some of their effects. For example, the 5 alpha-reduced metabolite of testosterone (T), dihydrotesterone, can be further converted to 5 alpha-androstane,17beta-diol-3 alpha-diol (3 alpha-diol) and 5 alpha-androstane,17beta-diol-3beta-diol (3beta-diol), both of which bind with high affinity to the beta isomer of the intracellular estrogen receptor beta (ER beta). However, androsterone, another metabolite of T, does not bind well to ER beta. To investigate the effects of T metabolites, male rats were subjected to gonadectomy then implanted with silastic capsules of 3 alpha-diol, 3beta-diol, androsterone, or oil control. After recovery, the rats were tested in elevated plus maze (EPM), light/dark transition (LD), and Morris water maze (MWM). 3 alpha-diol both decreased anxiety-like behavior in the EPM and LD, and increased cognition in MWM, while 3beta-diol improved cognition in MWM, but had no effects on anxiety behavior, compared to vehicle or androsterone. These data suggest that the actions of 3 alpha-diol and 3beta-diol at ER beta may be responsible for some of testosterone's anti-anxiety and cognitive-enhancing effects.

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats.

Androgen levels decline with aging. Some androgens may exert anti-anxiety and cognitive-enhancing effects; however, determining which androgens have anxiolytic-like and/or mnemonic effects is of interest given the different mechanisms that may underlie some of their effects. For example, the 5 alpha-reduced metabolite of testosterone (T), dihydrotesterone, can be further converted to 5 alpha-androstane,17beta-diol-3 alpha-diol (3 alpha-diol) and 5 alpha-androstane,17beta-diol-3beta-diol (3beta-diol), both of which bind with high affinity to the beta isomer of the intracellular estrogen receptor beta (ER beta). However, androsterone, another metabolite of T, does not bind well to ER beta. To investigate the effects of T metabolites, male rats were subjected to gonadectomy then implanted with silastic capsules of 3 alpha-diol, 3beta-diol, androsterone, or oil control. After recovery, the rats were tested in elevated plus maze (EPM), light/dark transition (LD), and Morris water maze (MWM). 3 alpha-diol both decreased anxiety-like behavior in the EPM and LD, and increased cognition in MWM, while 3beta-diol improved cognition in MWM, but had no effects on anxiety behavior, compared to vehicle or androsterone. These data suggest that the actions of 3 alpha-diol and 3beta-diol at ER beta may be responsible for some of testosterone's anti-anxiety and cognitive-enhancing effects.

Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice.

Testosterone (T) and its metabolites may underlie some beneficial effects for anxiety and cognition, but the mechanisms for these effects are unclear. T is reduced to dihydrotestosterone (DHT), which can be converted to 5alpha-androstane,3alpha,17beta-diol (3alpha-diol) and/or 5alpha-androstane-3beta,17beta-diol (3beta-diol). Additionally, T can be converted to androstenedione, and then to androsterone. These metabolites bind with varying affinity to androgen receptors (ARs; T and DHT), estrogen receptors (ERbeta; 3alpha-diol, 3beta-diol), or GABA(A)/benzodiazepine receptors (GBRs; 3alpha-diol, androsterone). Three experiments were performed to investigate the hypothesis that reduced anxiety-like and enhanced cognitive performance may be due in part to actions of T metabolites at ERbeta. Experiment 1: Gonadectomized (GDX) wildtype and ERbeta knockout mice (betaERKO) were subcutaneously (SC) administered 3alpha-diol, 3beta-diol, androsterone, or oil vehicle at weekly intervals, and tested in anxiety tasks (open field, elevated plus maze, light-dark transition) or for cognitive performance in the object recognition task. Experiment 2: GDX rats were administered SC 3alpha-diol, 3beta-diol, androsterone, or oil vehicle, and tested in the same tasks. Experiment 3: GDX rats were androsterone- or vehicle-primed and administered an antagonist of ARs (flutamide), ERs (tamoxifen), or GBRs (flumazenil), or vehicle and then tested in the elevated plus maze. Both rats and wildtype mice, but not betaERKO mice, consistently had reduced anxiety and improved performance in the object recognition task. Androsterone was only effective at reducing anxiety-like behavior in the elevated plus maze and this effect was modestly reduced by flumazenil administration. Thus, actions at ERbeta may be required for T's anxiety-reducing and cognitive-enhancing effects.

Androgen administration to aged male mice increases anti-anxiety behavior and enhances cognitive performance.

Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E(2)), and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17beta-diol (3alpha-diol). To ascertain whether actions of the neuroactive metabolite of T, 3alpha-diol, mediates cognitive and affective behaviors, intact, aged male C57/B6 mice (24 month old) as well as young, intact and gonadectomized (GDX; 12 week old) mice were administered s.c. T, 3alpha-diol, E(2), or sesame oil vehicle (1 mg/kg; n=4-5/group) at weekly intervals and 1 h later mice were tested in the activity box, roto-rod, open field, elevated plus maze, zero maze, mirror maze, dark-light transition, forced swim, or Vogel tasks. Mice were trained in the inhibitory avoidance or conditioned contextual fear and were administered hormones following training and then were tested. After the last test occasion, tissues were collected for evaluation of hormone levels and effects on gamma-aminobutyric acid (GABA)-stimulated chloride flux. T, 3alpha-diol, or E(2) increased anti-anxiety and antidepressant behavior of aged, intact mice in the open field, light-dark transition, mirror maze, and forced swim tasks. T or 3alpha-diol, but not E(2), enhanced anti-anxiety behavior in the elevated plus maze, zero maze, and the Vogel task, and increased motor behavior in the activity monitor, latency to fall in the Roto-rod task, and cognitive performance in the hippocampally-mediated, but not the amygdala-mediated, portion of the conditioned fear task and in the inhibitory avoidance task. Anti-anxiety and enhanced cognitive performance was associated with regimen that increased plasma and hippocampal 3alpha-diol levels and GABA-stimulated chloride flux. Similar patterns were seen among young, adult GDX but not in intact mice. Thus, 3alpha-diol can enhance affective and cognitive behavior of male mice.

Sexual experience of male rats influences anxiety-like behavior and androgen levels.

There is a wide body of literature to suggest that sexual experience may influence androgen secretion in various species, in turn, androgens may also influence anxiety. We hypothesized that sexual experience may alter anxiety behavior and secretion of endogenous androgens. Experiment 1: anxiety behavior of rats with a history of sexual experience was compared to that of sexually-inexperienced, naïve male rats. Sexually-experienced rats showed less anxiety-like behavior in the open field and elevated plus maze, and exhibited increased plasma and hippocampal testosterone (T) levels. Experiment 2: the effects of recent sexual experience on anxiety behavior of sexually-experienced male rats, sexually-responsive but inexperienced male rats, and sexually-unresponsive, inexperienced male rats exposed to a receptive female immediately prior to testing was examined. Recent sexual experience significantly decreased anxiety-like behavior in the open field, elevated plus maze, and the elevated zero maze tasks, and tended to decrease anxiety-like behavior in the light-dark task. Rats with recent sexual experience exhibited increased plasma and hippocampal T levels. Experiment 3: to examine the effect of recent sexual experience, anxiety behavior of rats with a history of sexual experience that received sexual experience with a stimulus female immediately prior to testing was compared to that of rats with a history of sexual experience that did not receive sexual experience immediately prior to behavioral testing. Experienced rats that were exposed to a female prior to testing showed decreased anxiety-like behavior in the open field, elevated plus maze, and light-dark transition tasks, and showed increased plasma and hypothalamic, T and 3alpha-diol, and increased hippocampal T. Thus, sexual experience is associated with lower levels of anxiety-like behavior and higher levels of androgen secretion.

Androgens' effects to enhance learning may be mediated in part through actions at estrogen receptor-beta in the hippocampus.

Testosterone (T) may enhance cognitive performance. However, its mechanisms are not well understood. First, we hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and/or 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol-administration directly to the hippocampus should enhance learning and memory in the inhibitory avoidance task. In order to test this hypothesis, gonadectomized (GDX) male rats were administered T, DHT, or 3alpha-diol via intrahippocampal inserts immediately following training in the inhibitory avoidance task. We found that T tended to increase, and DHT and 3alpha-diol significantly increased, performance in the inhibitory avoidance task compared to vehicle-administered GDX rats. Second, we hypothesized that, if androgens' effects are due in part to actions of 3alpha-diol in the hippocampus, then systemic or intrahippocampal administration of 3alpha-diol should significantly enhance cognitive performance of GDX male rats. Third, we hypothesized that, if androgen metabolites can have actions at estrogen receptors (ERs) in the hippocampus, then administration of ER antisense oligonucleotides (AS-ODNs) directly to the hippocampus of GDX, 3alpha-diol replaced, rats would decrease learning in the inhibitory avoidance task. We found that intrahippocampal administration of AS-ODNs for ERbeta, but not ERalpha, significantly decreased learning and memory of 3alpha-diol replaced rats. Together, these findings suggest that T's effects to enhance learning and memory may take place, in part, through actions of its metabolite, 3alpha-diol, at ERbeta in the dorsal hippocampus.

Androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks may involve actions at intracellular androgen receptors in the dorsal hippocampus.

Androgens can have performance-enhancing effects in some cognitive tasks, but the mechanism of these effects has not been established. Experiments examined whether androgens' actions to bind to intracellular androgen receptors (ARs) in the hippocampus are necessary to enhance cognitive performance in the inhibitory avoidance and water maze tasks. If androgens' binding at ARs are essential, then blocking them through intrahippocampal administration of flutamide, an AR receptor antagonist, should attenuate androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks. In Experiments 1 and 2, flutamide was administered through intrahippocampal inserts to intact male rats immediately pre- and post-training in the inhibitory avoidance and water maze tasks. Both pre- and post-training administration of flutamide to the dorsal hippocampus, but not missed sites, produced significantly poorer performance in the inhibitory avoidance and water maze tasks, without influencing control measures such as flinch/jump threshold or swim speed. In Experiment 3, flutamide administration to the hippocampus was delayed two hours following training in the inhibitory avoidance and water maze tasks. There was no significant effect of delayed administration of flutamide on performance in either of these tasks. Together, these findings suggest that blocking ARs in the dorsal hippocampus with flutamide administration immediately pre- or post-training can produce decrements in cognitive performance, which implies that androgens' performance-enhancing effects may occur, in part, through binding at intracellular androgen receptors in the dorsal hippocampus.

NorthEast Under/graduate Research Organization for Neuroscience (NEURON): Our Third New York City Meeting.

The NorthEast Under/graduate Research Organization for Neuroscience (N.E.U.R.O.N.) promotes preparation, education, and undergraduate research in Neuroscience. The N.E.U.R.O.N. Conference was initially held at undergraduate institutions primarily in New England. Then, for the previous two years, to broaden its impact and increase diversity, the meeting moved to Hunter College, CUNY, New York. This year represents the first year in which two N.E.U.R.O.N. meetings were held, one in Boston and one in New York City. The following is a report of the New York City meeting which was held at Hunter College on April 28, 2007. Eminent Neuroscientist, Dr. Carol Sue Carter, of the University of Illinois at Chicago, delivered the keynote address. The meeting also included the second bestowal of the Suzannah Bliss Tieman Research Awards for outstanding poster presentations and a workshop aimed at increasing minority participation in Neuroscience research. These highlights and future plans for N.E.U.R.O.N. are discussed.

Intrahippocampal administration of an androgen receptor antagonist, flutamide, can increase anxiety-like behavior in intact and DHT-replaced male rats.

Testosterone (T) and its 5alpha-reduced metabolite, dihydrotestosterone (DHT), can decrease anxiety-like behavior; however, the mechanisms underlying these effects have not been established. First, we hypothesized that if T reduces anxiety-like behavior through actions of its 5alpha-reduced metabolite, DHT, then gonadectomy (GDX) would increase anxiety-like behavior, an effect which would be reversed by systemic administration of DHT. Second, we hypothesized that if T and DHT reduce anxiety-like behavior in part through actions at intracellular androgen receptors in the hippocampus, then administration of an androgen receptor antagonist, flutamide, directly to the hippocampus should increase anxiety-like behavior of intact and DHT-replaced, but not GDX, male rats. Inserts that were empty or contained flutamide were applied directly to the dorsal hippocampus of intact, GDX, or GDX and DHT-replaced rats 2 h prior to testing in the open field, elevated plus maze, or defensive freezing tasks. GDX rats exhibited significantly more anxiety-like behaviors than intact or DHT-replaced rats. Intact and DHT-replaced rats administered flutamide to the hippocampus showed significantly more anxiety-like behavior than did intact and DHT-replaced controls. However, flutamide alone did not increase anxiety-like behavior of GDX rats. Together, these findings suggest that androgens can decrease anxiety-like behavior of male rats in part through DHT's actions at androgen receptors in the hippocampus.

Testosterone's anti-anxiety and analgesic effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus.

Although testosterone (T) may have effects to enhance analgesia and reduce anxiety, its effects and mechanisms are not well understood. We hypothesized that if T's anti-anxiety and analgesic effects are due in part to actions of its 5alpha-reduced metabolite (dihydrotestosterone-DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite (3alpha-androstanediol-3alpha-diol), in the hippocampus, then androgen regimens that increase levels of these metabolites in the hippocampus should produce anti-anxiety behavior, and analgesic effects, in gonadectomized (GDX) male rats. In Experiment 1, GDX rats were administered T, DHT, 3alpha-diol (1 mg/kg, SC), or vehicle. In Experiment 2, GDX rats had T, DHT, 3alpha-diol-containing inserts, or empty control inserts applied to the dorsal hippocampus immediately prior to behavioral testing. Androgen-administered rats (SC or intrahippocampal) showed significantly more exploratory behavior in the open field and elevated plus maze, less freezing in response to shock, and longer tailflick and pawlick latencies. These findings suggest that T's anti-anxiety effects may be due in part to actions of its 5alpha-reduced metabolites in the dorsal hippocampus.

Testosterone's analgesic, anxiolytic, and cognitive-enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus.

Although testosterone (T) may decrease anxiety and enhance cognitive performance, its mechanisms are not well understood. The authors hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol administration should produce similar behavioral effects concomitant with elevating T metabolites in the hippocampus. Gonadectomized male rats administered T, DHT, or 3alpha-diol via Silastic capsules or intrahippocampal infusions had greater analgesia (tail flick, paw lick), less anxiety behavior (plus-maze, open field, defensive freezing), and better learning (inhibitory avoidance) compared with vehicle control rats. Only 3alpha-diol levels in the hippocampus were consistently elevated in conjunction with these behavioral effects.

Testosterone's metabolism in the hippocampus may mediate its anti-anxiety effects in male rats.

Androgens may mediate anxiety behaviors; however, these effects and mechanisms of androgens are not well understood. The following experiments investigated whether testosterone (T)'s effects on anxiety behavior are mediated by its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) reduced metabolite 3alpha-androstanediol (3alpha-diol). In Experiment 1, gonadally-intact adult male rats and gonadectomized (GDX), DHT-replaced rats had similar low levels of anxiety behavior in the open field and elevated plus maze and fear behavior in the defensive freezing task compared with GDX control rats. In Experiment 2, intact or DHT-replaced rats that received blank inserts to the hippocampus demonstrated less anxiety behavior than did rats administered an implant of indomethacin, a 3alpha-HSD inhibitor, to the dorsal hippocampus. These data indicate that T's 5alpha-reduced metabolite, DHT, can reduce anxiety behavior and that blocking metabolism to 3alpha-diol in the hippocampus can attenuate these effects.

Mnemonic effects of testosterone and its 5alpha-reduced metabolites in the conditioned fear and inhibitory avoidance tasks.

Experiments were conducted to examine whether performance in hippocampally-mediated learning tasks is influenced by testosterone (T) and/or its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and 3alpha-androstanediol (3alpha-diol). Performance in the conditioned fear and inhibitory avoidance tasks were examined in intact and gonadectomized (GDX), androgen-replaced rats. In Experiment 1, the behavior of intact and GDX rats in the conditioned fear paradigm were compared. GDX rats spent more time freezing, an index of increased learning, in the context, hippocampally-mediated task, but not in the cued, amygdala-mediated task. In Experiment 2, GDX rats were administered T, DHT, 3alpha-diol, estrogen (E2), or vehicle 1 mg/kg sc after training in the conditioned fear paradigm. T-, 3alpha-diol-, or E2-, compared with vehicle-administered rats, spent significantly more time freezing in the contextual, but not the cued, condition. In Experiment 3, intact compared with GDX rats had significantly longer crossover latencies, indicating better performance, in the inhibitory avoidance task. In Experiment 4, T, DHT, 3alpha-diol, or vehicle 1 mg/kg sc was administered to GDX rats immediately following training in the inhibitory avoidance task. Rats administered T, DHT, or 3alpha-diol had significantly longer crossover latencies compared with vehicle controls. In Experiment 5, androgen levels in the hippocampus were elevated 1 h following administration, when androgen exposure is essential for consolidation. These data indicate that androgens effects to enhance learning may be mediated in part by actions of 5alpha-reduced metabolites in the hippocampus.

5alpha-reduced androgens may have actions in the hippocampus to enhance cognitive performance of male rats.

Androgens may improve cognitive performance; however, these effects and mechanisms of androgens are not well understood. Whether testosterone's (T) effects on cognitive performance are mediated by its 5alpha-reduced, non-aromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) reduced metabolite 3alpha-androstanediol (3alpha-diol), was investigated. In Experiment 1, male rats that were gonadally intact, or gonadectomized (GDX) and DHT-replaced with a silastic capsule, had better performance in the inhibitory avoidance task, and higher plasma DHT and 3alpha-diol levels, compared to GDX rats. In Experiments 2-4, intra-hippocampal indomethacin, a 3alpha-HSD inhibitor, to intact or DHT-replaced, but not GDX, rats decreased performance in the inhibitory avoidance task and reduced hippocampal 3alpha-diol levels compared to that observed in rats with control implants. Thus, the 5alpha-reduced androgen DHT has cognitive-enhancing effects, independent of E(2), which are attenuated by a 3alpha-HSD inhibitor, indomethacin. These results suggest that 5alpha-reduced androgens may have actions in the hippocampus to improve cognitive performance.

Northeast Under/graduate Organization for Neuroscience, A Regional Neuroscience Meeting for Undergraduates, Graduate Students, and Faculty.

The Northeast Under/graduate Organization for Neuroscience (N.E.U.R.O.N.) was established in 1996 to provide a forum for undergraduate and graduate students and faculty in neuroscience to interact with each other. N.E.U.R.O.N. organizes a yearly one-day conference in the Northeast. While scientific meetings exist that serve the purpose of enhancing undergraduate research or neuroscience research, N.E.U.R.O.N. is unique in that it is a small, local conference, aimed specifically at undergraduates looking to pursue careers in neuroscience. During the conference, participants attend workshops, poster sessions, and a keynote address that provide them with information about current topics in neuroscience. Trainees gain valuable experience presenting scientific research in poster sessions and make connections with colleagues.