Sex Differences in the Spatial Behavior Functions of Adult-Born Neurons in Rats

Abstract

Adult neurogenesis modifies hippocampal circuits and behavior, but removing newborn neurons does not consistently alter spatial processing, a core function of the hippocampus. Additionally, little is known about sex differences in neurogenesis since few studies have compared males and females. Since adult-born neurons regulate the stress response, we hypothesized that spatial functions may be more prominent under aversive conditions and may differ between males and females given sex differences in stress responding. We therefore trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. In the standard water maze, ablating neurogenesis did not alter spatial learning in either sex. However, in cold water, ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape the maze and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment (Fos expression) of the dorsal hippocampus than males, particularly in cold water. However, blocking neurogenesis did not alter Fos expression in either sex. Finally, morphologic analyses revealed greater experience-dependent plasticity in males. Adult-born neurons in males and females had similar morphology at baseline but training increased spine density and reduced presynaptic terminal size, specifically in males. Collectively, these findings indicate that adult-born neurons contribute to spatial learning in stressful conditions and they provide new evidence for sex differences in their behavioral functions.

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fibre plasticity in male but not female mice

“…As with the mossy fibre terminals, iTBS effects on filopodia were also specific to males. These findings align with recent evidence that water maze training also induces greater spine addition and presynaptic bouton atrophy in males than in females (O'Leary et al, 2022). It has also been shown previously that apical dendrites of CA3 pyramidal neurons in males show greater atrophy than female neurons after chronic stress (Galea et al, 1997).…”

“…Future studies can directly examine iTBS's effect on hippocampal synaptic transmission and memory. Given that there are sex differences in susceptibility to depression (Issler & Nestler, 2018;Radloff & Rae, 1979), as well as functions of neurogenesis (O'Leary et al, 2022) and iTBS sensitivity (present study), it raises the question of whether TMS can be targeted for hippocampaldependent cognitive disorders in a sex-specific fashion.…”

Inhibition of Hippocampal Neurogenesis Starting in Adolescence Increases Anxiodepressive Behaviors Amid Stress

“…Although enhanced HPA reactivity was originally discovered in TK mice (Snyder et al, 2011), two recently published reports show a more complicated picture in rats. One finds increased HPA reactivity to stress in male TK rats (Silveira-Rosa et al, 2022), whereas the other finds similar HPA reactivity between male WT and TK rats (O'Leary et al, 2022), which our study also supports. The reason for these discrepancies is unknown but may be due to either strain differences, duration and type of stressor, or additional methodological concerns.…”

“…We chose male rats to maximize sample size in our litter group due to unbalanced male and female generation and wanting to avoid using multiple litter groups at different times ( Lazic and Essioux, 2013 ). This exclusion of females though is particularly important as sex differences have been reported on the effects of developmental stress on adult anxiodepressive behavior ( Goodwill et al, 2019 ; Lovelock and Deak, 2019 ), stress effects on new neuron generation, survival, and activation ( Yagi and Galea, 2019 ; O’Leary et al, 2022 ), and behavioral consequences following neurogenesis ablation ( O’Leary et al, 2022 ; Silveira-Rosa et al, 2022 ; Waters et al, 2022 ). Other studies have shown comparable effects of neurogenesis ablation across sexes ( Huckleberry et al, 2018 ; Seib et al, 2018 ; Cope et al, 2020 ), and it is unknown how our adolescent manipulations would have affected adult anxiodepressive behaviors in female rats.…”

Sprague-Dawley rats differ in responses to medial perforant path paired pulse and tetanic activation as a function of sex and age

“…The higher PENK-cell proportion in females may support their greater intrinsic excitability. Based on the data from mice MPP-supported spatial and nonspatial representations might be predicted to be less sparse, but possibly more robust, in female rats than males (see for example O’Leary et al 21 , Olave et al 22 Zhvania et al 23 ). Experimental evidence with respect to place field and episodic representation in female versus male rats is needed.…”