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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 on 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.

Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both male and female animals in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories. LINKED ARTICLESThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-20 Abbreviations 5-HTT, 5-HT transporter; 8-OH-DPAT, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; Akt1, V-akt murine thymoma viral oncogene homologue 1; BDNF, brain-derived neurotrophic factor; BTBR, BTBR T + tf/J; CMS, chronic mild stress; COMT, catechol-O-methyltransferase-deficient mice; CR, conditioned response; CRF, corticotrophinreleasing factor; CS, conditioned stimulus; D1 receptor, dopamine 1 receptor; D2 receptor, dopamine 2 receptor; DISC1, disrupted-in-schizophrenia 1; Ehmt1, euchromatin histone methyltransferase 1; FBGRKO, forebrain glucocorticoid type II receptor (NR3C1) knockout; FSL, flinders sensitive rat line; FST, forced swim test; GSK3, glycogen synthase kinase 3; HAB, high anxiety-related behaviour rats; ICSS, intracranial self-stimulation; LAB, low anxiety-related behaviour rats; LI, latent inhibition; Mthfr, methylenetetrahydrofolate reductase; OCD, obsessive-compulsive disorder; PPI, prepulse inhibition; PTSD, post-traumatic stress disorder; SSRI, selective 5-HT re-uptake inhibitors; US, unconditioned stimulus; WKY, Wistar Kyoto IntroductionThe total disease burden for neuropsychiatric disorders in the European Union has been recently ...

Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiological sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clinical research documents sex differences in brain anatomy, chemistry and function, as well as in stress and drug responses. For example, some clinical studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioural aspects, as well as neurochemical, neurobiological and pharmacological findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behaviour, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochemical responses were differently affected in males and females, ultimately producing sex-dependent behavioural effects. In addition, Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochemical and behavioural alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.Men and women differ in the occurrence and symptomatology of several psychiatric disorders. Specifically, major depression, which is a significant cause of morbidity worldwide, is twice as common in females as in males [1]. Interestingly, prior to puberty, there are no sex differences in rates of major depression. Many theories, biological, psychosocial and sociological, attempt to explain this dramatic increase in the prevalence of depression among women, but none is fully satisfactory. Furthermore, while the preponderance of women suffering from depressive disorders is well-established, considerably less attention has been given to gender differences in the presentation and features of depression and in response to antidepressant treatment. This is not unrelated to the fact that women were under-represented in clinical trials prior to 1993 [2].A further difficulty is that the neurobiology of depression itself is still not fully understood. Most reports implicate abnormalities in the monoaminergic systems (i.e. serotonergic, noradrenergic and dopaminergic), but recent data show that many other systems are also involved in the pathophysiology of depression [3]. For example, depression is now commonly viewed as an impairment of neural plas...

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Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer's-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function.Tau | stress | hippocampus | depression | memory deficits T he cytoskeletal protein Tau is implicated in the establishment of Alzheimer's disease (AD) (1) as well as excitotoxicity (1) and, more recently, epilepsy (2, 3). Exposure to stressful conditions induces depressive behavior and memory deficits in both rodents and humans (4-8). Studies in rodents have shown that chronic stress triggers Tau hyperphosphorylation, a key pathogenic mechanism in AD, and results in cognitive and mood deficits (9-13); however, those studies do not provide direct evidence for a role of Tau in stress-evoked brain pathology. Given that Tau plays an important role in regulating neuronal architecture and function through its interaction with various cellular targets (e.g., tubulin and Fyn) (14), we hypothesized that Tau mediates the deleterious actions of stress on brain structure and function.To test the above hypothesis, we compared the impact of chronic unpredictable stress (CUS) (11, 15) in mice carrying a null mutation of the mapt gene [Tau knockout (Tau-KO) mice] (16) with their wild-type (WT) littermates. Three well-characterized behavioral endpoints (cognition, coping styles, and anxiety) that are disrupted by CUS served as the primary assay endpoints; these were complemented with measures of hippocampal structural and functional integrity. The hippocampus is a central component of the neurocircuitries that control these behaviors and displays overt lesions in both stress-and Tau-related pathologies; in the latter, the hippocampus is one of the earliest brain regions to show signs of neurodegeneration (1,4,7,(10)(11)(12)(13)17). ResultsDeleterious Effects of Stress on Memory and Mood Are Abrogated in the Absence of Tau Protein. Cognition, mood, and anxiety are interdependent behavioral domains that exhibit complex interactions (5). Different forms of memory were assessed after exposure of WT and Tau-KO mice to the CUS paradigm; the test battery included the Y-maze, Morris water maze (MWM), and the novel object recognition test (NOR). Anxiety was evaluated using the elevated plus maze (EPM), and coping styles and anhedonia were assessed using the forced swim test (FST) and the sucrose consumption test (SCT).Two-way ANOVA ...

Women are more likely than men to suffer from stress-related mental disorders, such as depression. In the present experiments, we identified sex differences in one of the most common animal models of depression, that of learned helplessness. Male and female rats were trained to escape a mild footshock each day for 7 days (controllable stress). Each rat was yoked to another rat that could not escape (uncontrollable stress), but was exposed to the same amount of shock. One day later, all stressed rats and unstressed controls were tested on a more difficult escape task in a different context. Most males exposed to uncontrollable stress did not learn to escape and were therefore helpless. In contrast, most females did learn to escape on the more difficult escape task, irrespective of whether they had been exposed to controllable or uncontrollable stress. The sex differences in helplessness behavior were not dependent on the presence of sex hormones in adulthood, because neither ovariectomy of females nor castration of males abolished them. The absence of helplessness in females was neither dependent on organizational effects of testosterone during the day of birth, because masculinized females did not express helplessness as adults. Thus, sex differences in helplessness behavior are independent of gonadal hormones in adulthood and testosterone exposure during perinatal development. Learned helplessness may not constitute a valid model for depressive behavior in women, at least as reflected by the response of female rats to operant conditioning procedures after stressful experience.

In Japanese quail, as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increase dopamine release in the preoptic area. In quail, in vitro brain aromatase activity (AA) is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain AA, which was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that AA is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activities. These data challenge established views about the causal relationships among dopamine, estrogen action, and male sexual behavior.