Sex differences in learning processes of classical and operant conditioning

Abstract

Males and females learn and remember differently at different times in their lives. These differences occur in most species, from invertebrates to humans. We review here sex differences as they occur in laboratory rodent species. We focus on classical and operant conditioning paradigms, including classical eyeblink conditioning, fear-conditioning, active avoidance and conditioned taste aversion. Sex differences have been reported during acquisition, retention and extinction in most of these paradigms. In general, females perform better than males in the classical eyeblink conditioning, in fear-potentiated startle and in most operant conditioning tasks, such as the active avoidance test. However, in the classical fear-conditioning paradigm, in certain lever-pressing paradigms and in the conditioned taste aversion, males outperform females or are more resistant to extinction. Most sex differences in conditioning are dependent on organizational effects of gonadal hormones during early development of the brain, in addition to modulation by activational effects during puberty and adulthood. Critically, sex differences in performance account for some of the reported effects on learning and these are discussed throughout the review. Because so many mental disorders are more prevalent in one sex than the other, it is important to consider sex differences in learning when applying animal models of learning for these disorders. Finally, we discuss how sex differences in learning continue to alter the brain throughout the lifespan. Thus, sex differences in learning are not only mediated by sex differences in the brain, but also contribute to them.

Figure 1. Females outperform males in eyeblink conditioning

a. During eyeblink conditioning, a conditioned stimulus (CS) of white noise is paired with an unconditioned stimulus (US; periorbital stimulation), which elicits an eyeblink response. In the non-hippocampal dependent task of delay conditioning the two conditioning stimuli overlap in time. In the hippocampal-dependent task of trace conditioning the two conditioning stimuli are separated by a trace interval or “temporal gap” of 500 ms. As an animal learns that the two stimuli are associated, it blinks in anticipation of the US. Eyeblinks are detected by an increase in the magnitude of the electromyographical (EMG) response of the muscle of the upper eyelid. Those blinks that occur close to the US are considered conditioned responses (CRs). The electrophysiological record shows an example of a CR that occurred just prior to the onset of the US. b. Intact females emit more conditioned responses than intact males during trace eyeblink conditioning (p<0.05). In this experiment, all females were in diestrus on the first day of training. Rats were trained with 800 trials of trace eyeblink conditioning over a period of 4 days (200 trials/day). The sex difference is evident during the first two days of training [47].

Figure 2. Dendritic spines in the hippocampus might represent an anatomical background for learning

a. Representative pictures of pyramidal neurons in the CA1 area of the hippocampus stained with the Golgi impregnation technique (magnification 200×). Density of dendritic spines is measured in the basal and the apical dendrites of the pyramidal cells. A closer image (magnification 1000×) of dendritic spines in the apical dendrites of a female rat is shown [56]. b. Female rats in proestrus have higher densities of dendritic spines in the CA1 area of the hippocampus, in comparison to females in diestrus and in estrus and to intact males [55].

Figure 3. Associative learning increases neurogenesis in the male and female hippocampus

a. The density of adult generated cells (BrdU-labeled cells) in the dentate gyrus of the hippocampus is enhanced in rats trained with trace eyeblink conditioning, in comparison to untrained animals. The percent increase is greater in trained females (34%) than in trained males (17%). The density of new cells in untrained females is lower than that in untrained males (significant differences are noted with an *) [47]. b. A representative picture of the dentate gyrus is shown (magnified 20×). In the smaller panel (magnified 1000×), the new cells in the dentate gyrus of the adult hippocampus are stained in brown (BrdU-labeled cells). The hippocampal slice was counterstained with cresyl violet (cells shown in purple).

Figure 4. Females outperform males in the active avoidance task

a. Gonadally-intact females escape sooner than gonadally-intact males in active avoidance (p<0.05). Females were in various stages of the estrous cycle at the time of testing. Rats were trained to avoid a mild footshock by passing though the doorway of the shuttle box twice (FR2), for 30 trials in one day [84]. b. Ovariectomy of adult females in adulthood has no effect on active avoidance. Gonadally-intact and ovariectomized females exhibit the same escape latencies when they are trained to avoid a mild footshock by passing twice though the doorway of the shuttle box (FR2), for 30 trials in one day [84]. c. Castrated adult males learn to escape sooner the mild footshock in the FR2 task, in comparison to gonadally-intact adult males (p<0.05). Rats were trained to avoid a mild footshock by passing though the doorway of the shuttle box twice (FR2), for 30 trials in one day [84].