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Additional file 1: Fig. S1. Heatmaps showing all correlations and cytoscape graphs showing significant correlations ≥0.7 between inflammatory marker correlations between the ventral hippocampus and basolateral amygdala in male and female adolescent (A-C), young adult (D-F), and middle-aged (G-I) rats after cognitive bias testing. The thickness of the lines in B, C, E, F, H, and I are related to the strength of the correlation (stronger is thicker), whereas the color relates to the valence (positive (red) or negative (blue)) of the correlation. Correlations of inflammatory marker levels within the ventral hippocampus and basolateral amygdala were largely positive in all age groups, although correlations between regions were more negative in male and female young adults compared to the other age groups. In adolescence, there was a sex difference in the correlations between basolateral amygdala IL-6 and cytokines (IFN-γ, IL-1β, IL-4, IL-5, IL-10, IL-13, TNF-α) in the ventral hippocampus, with positive correlations in adolescent females compared to negative correlations in adolescent males. n=7-11 per group. Fig. S2. Mean (±SEM) percentage of time spent freezing (A) and negative cognitive bias discrimination scores (B) of male and female adolescent, young adult, and middle-aged test rats and no-shock controls. Negative cognitive bias scores > 0 are rats with a negative cognitive bias and scores ≤ 0 are rats that had a neutral or positive cognitive bias. Test rats have a greater negative cognitive bias than no-shock controls. In test rats, young adults and middle-aged rats had greater negative cognitive bias scores than adolescents, and males had greater negative cognitive bias than females in middle-age. *indicates p’s

Menopause is associated with cognitive decline, and hormone therapies (HT) may improve cognition depending on type, and timing of HT. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and all rats were trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor (TNF) α and the CXC chemokine ligand 1 (CXCL1) in nulliparous, but not primiparous, trained rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.

In women, breastfeeding generally results in reductions in anxiety and increased positive mood. However, approximately 10–15% of women experience depressed mood and increased anxiety during the first year postpartum. Recent research has demonstrated that offspring-exposure is important for the reduction in behaviours related to depression and anxiety in the mother. It remains to be determined whether these effects are due to factors related to pregnancy and/or pup-exposure, are associated with the degree of maternal behaviour by the mother towards offspring, or persist after weaning. To address these questions the present study used four groups of female rats; primiparous, nulliparous, primip-no-pups (primiparous females with pups permanently removed), and sensitized females. Depressive- and anxiety-like behaviours were assessed one week after weaning/pup-exposure (4 weeks after birth for primip-no-pups animals) using the Forced Swim Test for measures of depressive-like behaviour, and the Open Field Test and Elevated Plus Maze for measure of anxiety-like behaviour. Results demonstrate that primiparous females without pup-exposure have increased depressive-like, but not anxiety-like, behaviour compared to primiparous and sensitized females. In addition, kyphotic nursing by primiparous mothers was negatively related to behavioural measures of depression and anxiety. From this work is it clear that pup-exposure acts is important for reductions in depressive-like behaviour in parturient females. Further research is needed to determine the extent of these changes and the neural and hormonal correlates of these events

Postpartum depression affects approximately 15% of mothers. Unfortunately, treatment options for postpartum depression are limited. Pharmacological antidepressants such as fluoxetine (FLX) can be controversial due to inconclusive evidence of efficacy during the postpartum and concerns of neonatal exposure to antidepressants. Alternatively, non-pharmacological antidepressants such as exercise may be less controversial but its efficacy in postpartum depression is unclear. To investigate this, we treated rat dams daily with high levels of corticosterone (CORT; 40 mg/kg), to induce a depressive-like phenotype, or oil (vehicle for CORT) during the postpartum period. Within the oil and CORT conditions, four additional antidepressant conditions were created: 1. FLX (10 mg/kg) + exercise (voluntary access to running wheel); 2. FLX + no exercise; 3. Saline (vehicle for FLX) + exercise; 4. Saline + No exercise. We examined maternal care, depressive-like and anxiety-like behavior, stress reactivity, and hippocampal neurogenesis and dams were categorized as “high running” or “low running.” FLX treatment, alone or with high running, prevented CORT-induced disruptions in maternal care. As expected, CORT increased depressive-like behavior but exercise, regardless of running amount, reduced depressive-like behavior. Intriguingly, FLX, but not CORT, increased anxiety-like behavior, which was not mitigated by concurrent exercise. FLX treatment slightly but significantly facilitated serum CORT recovery after forced swim stress. CORT and FLX alone reduced neurogenesis, while exercise coupled with FLX increased density of doublecortin-expressing cells. High running increased density of doublecortin-expressing cells (immature neurons) in comparison to controls. Collectively, these findings indicate that FLX and exercise reverse different endophenotypes of depression in dams, which has translational implications for surveying treatment options of postpartum depression.

Adult hippocampal neurogenesis is often associated with hippocampus-dependent learning and memory. Throughout a new neuron’s development, it is differentially sensitive to factors that can influence its survival and functionality. Previous research shows that, spatial training that occurred 6 to 10 days after an injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), increased cell survival in male rats. Because sex differences in spatial cognition and hippocampal neurogenesis have been reported, it is unclear whether spatial training would influence hippocampal neurogenesis in the same way in males and females. Therefore, this study examined sex differences in hippocampal neurogenesis following training in a spatial task. Male and female rats were trained in the spatial or cued version of the Morris water maze task 6 to 10 days after one injection of BrdU (200mg/kg). Twenty days following BrdU injection, all animals were given a probe trial and perfused. Males performed better in the spatial, but not cue, task than females. Spatial training increased BrdU-labeled cells relative to cue training only in males, but both males and females showed greater activation of new cells (BrdU co-labeled with immediate early gene product zif268) after spatial training compared to cue training. Furthermore, performance during spatial training was positively correlated with cell activation in females but not males. This study shows that while spatial training differentially regulates hippocampal neurogenesis in males and females, the activity of new neurons in response to spatial memory retrieval is similar. These findings highlight the importance of sex on neural plasticity and cognition.

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU) and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the 8-arm radial arm maze. Twenty eight days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.