The effect of gonadal steroids on the behavioral and biochemical effects of hippocampal sympathetic ingrowth

doi:10.1016/0031-9384(90)90291-B

Physiology & Behavior

Volume 48, Issue 4, October 1990, Pages 507-513

https://doi.org/10.1016/0031-9384(90)90291-B Get rights and content

Abstract

Following cholinergic denervation of the hippocampal formation, via medial septal lesions, sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previous studies have demonstrated a detrimental effect of these fibers on recovery of a spatial-learning task in male but not female animals. In this study we assessed the role of circulating male sex hormones on the behavioral and biochemical effects of hippocampal sympathetic ingrowth (HSI). For the behavioral studies male Sprague-Dawley rats underwent either sham gonadectomy or gonadectomy and were taught a standard radial 8-arm maze task. Following attainment of criterion animals underwent one of three surgical procedures: sham surgery, MS lesions, MS lesions + ganglionectomy. MS lesions, regardless of the presence of HSI, were found to severely impair reacquisition of the task in both sham-gonadectomized and gonadectomized animals. As expected, in the sham-gonadectomized group, MSGx animals reacquired the task faster than the MS group. However, gonadectomy was found to block the detrimental effect of HSI on behavior. For the biochemical studies hippocampal norepinephrine (NE) and choline acetyltransferase (ChAT) were measured eight weeks after surgery in sham-gonadectomized and gonadectomized animals. MS lesions were found to significantly reduce the ChAT activity, regardless of circulating sex hormones. Gonadectomy was found to significantly reduce the level of NE associated with HSI, while having no effect on central NE in CON or MSGx animals. These studies suggest that circulating male sex hormones can influence both the behavioral and biochemical processes associated with HSI.

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Several studies that have investigated the activational role of steroids in cognitive behavior among males have demonstrated that castration leads to a decline in spatial and other types of working memory. In support of this, castrated rats show inhibited acquisition in the T maze and radial arm maze (Daniel et al., 2003; Harrell et al., 1990; Kritzer et al., 2001; Spritzer et al., 2008). Castrated rats demonstrate deficient acquisition of spatial tasks, even when stressors or motivational valence (i.e., aversive versus appetitive) of the task are mitigated (Locklear and Kritzer, 2014; McConnell et al., 2012).
In rodents, gonadal steroids play a critical yet variable role in behaviors such as social interaction and cognitive performance. Gonadal steroids organize sex differences observed in spatial working memory, while the absence of activational effects induced by castration generally impedes spatial learning and memory. Although male sexual behavior is typically inhibited following castration, a significant proportion of gonadectomized B6D2F1 hybrid males retains the complete repertoire of male reproductive behavior. In a prior study, amyloid precursor protein and tau, proteins involved in cognitive behavior, facilitated steroid-independent male sex behavior in B6D2F1 hybrid male mice. We used this strain to investigate the relationship between gonadal steroid-independent male sexual behavior and cognition. After identifying “maters” (animals retaining steroid-independent male sex behavior) and “non-maters,” we tested spatial memory in an 8-arm radial arm maze. Although neither group demonstrated a decrease in errors as a function of time, maters committed fewer errors compared to non-maters overall (p < 0.05). Maters also completed the maze more quickly than non-maters (p < 0.05). We measured mRNA expression of APP and MAPT as well as LEPR and D2R to probe potential roles of metabolism and motivation. Uniquely among maters, increased relative expression of D2R and LEPR in the hippocampus was associated with a longer latency to complete the maze during the last 3 or across all trials, respectively. These data demonstrate that maters outperform non-maters in the radial arm maze, warranting further study of potential differences in acquisition of spatial memory tasks or learning strategy between these groups.
Testosterone modulates spatial recognition memory in male rats
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Taken together, the results extend previous findings and indicate that testosterone modulates spatial performance on tasks that take advantage of the tendency of rodents to seek out novel spatial environments, but perhaps only under conditions with increased cognitive demand. Importantly, after sufficient training, orchidectomized rats eventually reach the same level of performance on spatial tasks exhibited by rats with testosterone (Daniel et al., 2003; Harrell et al., 1990; Hawley et al., 2012; Spritzer et al., 2008, 2011). Furthermore, the effects of testosterone on spatial cognition in male rodents appear rather modest, emerging only early in learning (Daniel et al., 2003; Spritzer et al., 2008, 2011) or, as appears to be the case for the current set of experiments, when the demands of the task become sufficiently challenging (Benice and Raber, 2009; Sandstrom et al., 2006).
A growing body of research indicates that testosterone influences spatial cognition in male rats; however, the overwhelming majority of studies have been conducted on tasks motivated by either food deprivation or water escape. The hippocampus-dependent version of the Y-maze task, which characterizes spatial recognition memory, capitalizes on the propensity of rats to gravitate toward novel spatial environments and is not contingent upon either appetite or the stress associated with water escape, two factors also affected by testosterone. Accordingly, the aim of the current study was to examine the effects of orchidectomy and subsequent testosterone treatment on spatial recognition memory. Orchidectomy did not impact spatial recognition memory when the delay between the information and retention trials of the Y-maze task was 24 h. Alternatively, on the second Y-maze task, which featured a 48-h delay between trials, orchidectomy reduced, and treatments that produced higher levels of testosterone restored, preference for the arm associated with the novel spatial environment. Importantly, there were no differences in activity levels as a function of orchidectomy or testosterone treatment on either of the two tasks. Consistent with previous findings, orchidectomy attenuated, and testosterone treatment restored, both body weight gain and the relative weight of the androgen-sensitive ischiocavernosus muscle, which confirmed the efficacy of orchidectomy and testosterone treatments on physiological outcomes. Therefore, testosterone influenced spatial cognition on a task that minimized the influence of non-mnemonic factors and took advantage of the innate preference of rodents to seek out novel spatial environments.
The effects of biological sex and gonadal hormones on learning strategy in adult rats
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While stage of the estrous cycle did not impact the performance of female rats, orchidectomy significantly impacted different facets of performance in male rats. Given the effects of estradiol in female rats on both spatial learning [62] and learning strategy [38], we expected the previously documented deficiencies in spatial cognition as a function of testosterone depletion to translate into less of a reliance on a hippocampus-dependent place strategy [63–72]. Results of the current study indicated that testicular hormones modulated learning, but not the preference for a place learning strategy.
When learning to navigate toward a goal in a spatial environment, rodents employ distinct learning strategies that are governed by specific regions of the brain. In the early stages of learning, adult male rats prefer a hippocampus-dependent place strategy over a striatum-dependent response strategy. Alternatively, female rats exhibit a preference for a place strategy only when circulating levels of estradiol are elevated. Notably, male rodents typically perform better than females on a variety of spatial learning tasks, which are mediated by the hippocampus. However, limited research has been done to determine if the previously reported male spatial advantage corresponds with a greater reliance on a place strategy, and, if the male preference for a place strategy is impacted by removal of testicular hormones. A dual-solution water T-maze task, which can be solved by adopting either a place or a response strategy, was employed to determine the effects of biological sex and hormonal status on learning strategy. In the first experiment, male rats made more correct arm choices than female rats during training and exhibited a bias for a place strategy on a probe trial. The results of the second experiment indicated that testicular hormones modulated arm choice accuracy during training, but not the preference for a place strategy. Together, these findings suggest that the previously reported male spatial advantage is associated with a greater reliance on a place strategy, and that only performance during the training phase of a dual-solution learning task is impacted by removal of testicular hormones.
Testosterone impairs the acquisition of an operant delayed alternation task in male rats
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The current study examined the effects of gonadectomy (GDX) and subsequent testosterone treatment of male Long-Evans rats on an operant variable delay spatial alternation task (DSA). Gonadally-intact rats (intact-B), GDX rats receiving implants that delivered a physiological level of testosterone (GDX-T), and GDX rats receiving blank implants (GDX-B) were tested for 25 sessions on a DSA task with variable inter-trial delays ranging from 0 to 18 s. Acquisition of the DSA task was found to be enhanced following GDX in a time and delay dependent manner. Both the GDX-T and the intact-B rats had lower performance accuracies across delays initially, relative to GDX-B rats, and this deficit persisted into subsequent testing sessions at longer delays. The GDX-T and intact-B rats also had a tendency to commit more perseverative errors during the early testing sessions, with both groups persisting in pressing a lever which had not been associated with reinforcement for at least two consecutive trials. However, both the GDX-T and intact-B groups were able to achieve performance accuracy similar to that of the GDX-B rats by the final sessions of testing. Overall, these results suggest that castration of adult male rats enhances their acquisition of an operant DSA task.
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Previous studies have shown that gonadectomy in adult male rats influences the acquisition and performance of spatial and other working memory tasks that depend in part on the medial prefrontal cortex and its dopamine innervation. Stimulated by previous findings that gonadectomy alters dopamine axon density in not only medial but several other prefrontal fields, the present studies asked whether gonadectomy might also broadly impact dopamine-dependent prefrontal functions, and whether these effects bore any relation to hormone modulation of mesoprefrontal dopamine afferents. Specifically, control, gonadectomized, and gonadectomized rats given estradiol or testosterone propionate were tested on a series of operant tasks that together measured medial prefrontal functions of spatial working memory, impulsivity and extradimensional set shifting and orbital prefrontal functions of reversal learning/perseveration and motivation. Afterwards, animals were sacrificed, their bulbospongiosus muscles were removed and weighed, their brains were processed for immunocytochemistry for the dopamine-synthesizing enzyme tyrosine hydroxylase, and axon densities were measured in orbital and medial prefrontal fields. Statistical evaluations of group effects on behavior and regression analyses comparing individual performance with muscle weights and axon density measures revealed androgen-reversible effects of gonadectomy on acquisition of spatial working memory and extradimensional set shifting that were correlated with bulbospongiosus weight and medial prefrontal dopamine axon density, estrogen-sensitive influences of gonadectomy on motivation and response withholding that were correlated with bulbospongiosus weight but not with dopamine innervation, and still other prefrontal functions, i.e., impulsivity, reversal learning, that were insensitive to gonadectomy and unrelated to gonadectomy-induced changes in muscle weight or prefrontal dopamine innervation.
Androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks may involve actions at intracellular androgen receptors in the dorsal hippocampus
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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.

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The effect of gonadal steroids on the behavioral and biochemical effects of hippocampal sympathetic ingrowth

Abstract

Horm. Behav.

Brain Res. Rev.

Brain Res.

Exp. Neurol.

Pharmacol. Biochem. Behav.

J. Biol. Chem.

Brain Res.

Brain Res. Bull.

Recovery of function from septal damage and the growth of sympathohippocampal fibers

Physiol. Psychol.

Histochemical fluorescence of tissue and brain monoamines results in 18 minutes using the sucrosephosphate glyoxylic acid (SPG) method

Neuroscience

The symmetrical maze: an automated closed field test series for rats

Behav. Res. Methods Instrum.