Research reportEffects of gonadal hormones and persistent pain on non-spatial working memory in male and female rats
Introduction
In humans as well as in experimental animals, the main gonadal hormones are androgen and estrogen. The effects of gonadal hormones on the central nervous system (CNS) have been defined as ‘organizational’ and ‘activational’ [35]. The former, due to the perinatal action of gonadal hormones, are permanent and different in the two sexes; these effects are evident not only in the primary and secondary sex characteristics, but also in the CNS where many structures are anatomically and functionally different between males and females [29], [36]. The activational effects are instead transient and depend on the gonadal hormone levels. Study of the various sex differences induced by gonadal hormones includes the analysis of cognitive aspects such as learning and memory processes [7], [27]. Women perform better than men on verbal and memory tasks, whereas men excel in spatial tasks [9], [10]. Rodents, commonly used to study cognitive functions, also show sex differences: males tend to perform better than females in a variety of spatial [28] and memory tasks [42], while females show a better performance in a visual memory test [15]. Studies of maze performance indicate that estradiol exerts an activational effect on spatial memory in females [25]; these actions have been attributed to the estrogen-induced effects on dendritic spine density and synapses numbers [18], [46], [47], neurotrophic mechanisms [13], [17], [44] and NMDA receptor protein levels [14] in the hippocampus, a brain area repeatedly shown to be involved in spatial performance, arousal, learning and memory. In addition to these functions, the hippocampal formation also participates in pain processes [3], [22]. Indeed hippocampal activity is changed by persistent pain and these effects are different in males and females [2], [5].
The purpose of the present study, conducted with a 2×2 test paradigm, was to determine whether gonadal hormones affect working memory, i.e. the type of memory whose impairment is first noted in Alzheimer's Disease in humans and which is impaired in aging rats [39]. In our case, working memory requires the rat to realize that an object in the experimental apparatus has been replaced by a novel one.
The Object Recognition Test (ORT) measures a form of non-spatial working memory, based on spontaneous exploratory activity, which may be considered episodic memory [11]. An important issue rarely considered in this type of experiment is the testing of animals under strictly physiological conditions. In particular, the testing of rodents during the light phase obliges the animals to perform cognitive tasks during their sleeping period. Restriction of food is also commonly used and the animals are rarely familiar with the testing apparatus.
We hypothesized that the ORT might induce different behavioural responses in male and female rats and that the lack of circulating gonadal hormones, as observed after gonadectomy, may change these responses. In addition, since painful conditions are known to change levels of attention and the ability to memorize [21], we tested ORT with male and female rats experiencing a tonic, long-lasting painful stimulus. In the first part of the experiment, intact and gonadectomized female and male rats were first placed in an open field with three objects and then were re-exposed to the same open field with a different combination of objects. In the second part of the experiment, the effect of a persistent nociceptive stimulation (formalin test) [3] applied just before the beginning of the test was evaluated.
Section snippets
Subjects
Sixty-four male and female Wistar rats, aged 3 months at the onset of behavioural testing (Harlan, Correzzana, Italy) were housed four per cage, same sex, to allow social interactions. They were given unlimited access to laboratory chow and water, and were maintained on a 12:12 light:dark cycle (light off at 7.00 h).
Gonadectomy: The rats were anaesthetised with pentobarbital (40 mg/kg, i.p.) and bilaterally gonadectomized (GDX) or subjected to a sham surgical procedure (Intact) as previously
Experimental Day 1: effects of sex and gonadectomy on object recognition (Trial 1)
Once inside the open field apparatus, the rats moved around in the cage approaching the three objects (sniffing, marking, licking) or simply walking around them. The latency of approach (Table 1) did not differ between the sexes; the significance of the factor Gonadectomy for OBJ 1 (P<0.006) was due to the lower latency of approach to this object in GDX animals than in intact ones. There were no differences for the other objects. The frequency of approach (Table 1) also did not differ between
Discussion
The main results of the present experiment are the sex- and GDX-induced differences in the behaviours related to the object recognition test apparatus and the modulatory effect on object recognition exerted by formalin treatment.
Acknowledgements
This work was supported by University of Siena and MURST (ex-40% funds).
References (47)
- et al.
Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats
Neuroscience
(1999) Sex differences in pain-induced effects on the septo-hippocampal system
Brain Res. Brain Res. Rev.
(1997)- et al.
Formalin-induced changes in adrenocorticotropic hormone and corticosterone plasma levels and hippocampal choline acetyltransferase activity in male and female rats
Neuroscience
(1996) - et al.
Gonadectomy and persistent pain differently affect hippocampal c-Fos expression in male and female rats
Neurosci. Lett.
(2000) - et al.
Sex-dependent effects of formalin and restraint on c-Fos expression in the septum and hippocampus of the rat
Neuroscience
(1997) - et al.
Effects of formalin pain on hippocampal c-Fos expression in male and female rats
Pharmacol. Biochem. Behav.
(1999) - et al.
A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data
Behav. Brain Res.
(1988) - et al.
Gonadal steroids as promoters of neuro-glial plasticity
Psychoneuroendocrinology
(1994) - et al.
Sex differences in memory performance in the object recognition test. Possible role of histamine receptors
Pharmacol. Biochem. Behav.
(1999) - et al.
Effects of estrogen and fimbria/fornix transection on p75NGFR and ChAT expression in the medial septum and diagonal band of Broca
Exp. Neurol.
(1992)
Effects of estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats
Brain Res.
Sex differences in animal tests of anxiety
Physiol. Behav.
Effects of hormone manipulations and exploration on sex differences in maze learning
Behav. Biol.
Avoidance versus focused attention and the perception of pain: differential effects for men and women
Pain
Responses in the CA1 region of the rat hippocampus to a noxious stimulus
Exp. Neurol.
Functions of the frontal cortex of the rat: a comparative review
Brain Res.
Effects of estradiol on radial arm maze performance of young and aged rats
Behav. Neural. Biol.
Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters
Horm. Behav.
Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning
Brain Res.
Performance and intelligence in hormonally different groups
Prog. Brain Res.
Estrogen affects performance of ovariectomized rats in a two-choice water-escape working memory task
Psychoneuroendocrinology
Developmental regulation of sex differences in the brain: can the role of gonadal steroids be redefined?
Neuroscience
Functional sex differences (‘sexual diergism’) of central nervous system cholinergic systems, vasopressin, and hypothalamic-pituitary- adrenal axis activity in mammals: a selective review
Brain Res. Brain Res. Rev.
Cited by (53)
Task-specific effects of biological sex and sex hormones on object recognition memories in a 6-hydroxydopamine-lesion model of Parkinson's disease in adult male and female rats
2022, Hormones and BehaviorCitation Excerpt :For the NOR task, hormone sensitivity has been extensively studied in female rats and potentiating or protective effects of estrogens have been generally found (Luine et al., 2003; Walf et al., 2006; Sutcliffe et al., 2007; Ghi et al., 1999; Wallace et al., 2006; Kim and Frick, 2017). Although fewer studies have examined the effects of gonadal hormones on NOR performance in males (Ceccarelli et al., 2001; Karlsson et al., 2015), previous studies from our lab have shown that NOR discrimination is significantly impaired by ORX for both shorter (1.5 h.) and longer (4 h.) intertrial delays and that these deficits are attenuated in ORXTP but not ORXE rats (Aubele et al., 2008). While TP can act as an androgen and/or be metabolized to estradiol, the absence of appreciable rescue in the ORXE group identified NOR discrimination as an androgen-sensitive process (Aubele et al., 2008).
Reducing local synthesis of estrogen in the tubular striatum promotes attraction to same-sex odors in female mice
2022, Hormones and BehaviorCitation Excerpt :Further, this behavioral assay does not require extensive prior training, which was particularly important for this study in which we used GDX to remove circulating gonadal hormones to allow for an unobscured examination of TuS-derived E2. Prior work indicates that GDX impairs acquisition of an operant learning-based, Go/No-Go odor discrimination task in both sexes (Kunkhyen et al., 2018), as well as cognition and memory more broadly (McEwen et al., 1997; Ceccarelli et al., 2001; Aubele et al., 2008; Dossat et al., 2017). Therefore, our experimental approach was intended to investigate odor-guided behavior while mitigating unnecessary cognitive demands.
Sexually Dimorphic Expression of Fear-conditioned Analgesia in Rats and Associated Alterations in the Endocannabinoid System in the Periaqueductal Grey
2022, NeuroscienceCitation Excerpt :Indeed, in a previous study in which male and female Sprague-Dawley rats were injected in the right hind paw with formalin and immediately after exposed to the conditioned place aversion test, the analysis of the locomotor activity during the 60 min trial showed that females exhibited significantly lower distance moved than males, as well as a tendency for a lower frequency of rearing (Jarrin et al., 2020). On the other hand, Ceccarelli and colleagues (2001) did not observe significant differences in rearing frequency between male and female Wistar rats treated with formalin and exposed to the conditioning phase of the object recognition test (Ceccarelli et al., 2001). Further studies should analyse the existence of sex differences in locomotor activity in the presence of nociceptive tone.
The Role of Sex and Sex Steroids in the Novel Object Recognition Task
2018, Handbook of Behavioral Neuroscience