Sex differences in anxiety-like behaviors in rats

ABSTRACTThe dentate gyrus (DG) of the hippocampus is important for cognitive and affective behaviors. However, the circuits underlying these behaviors are unclear. DG mossy cells (MCs) have been a focus of attention because of their excitatory synapses on the primary DG cell type, granule cells (GCs). However, MCs also activate DG GABAergic neurons which inhibit GCs. We took advantage of specific methods and a gain- and loss-of function strategy with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to study MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENTThe dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

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“…Notably, these results are consistent with sex differences in EPM behaviors (Belviranli et al, 2012;Scholl et al, 2019).…”

Section: Epmsupporting

confidence: 83%

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

Preprint

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“…In the present study, adult female rats developmentally exposed to Pb show increased anxiety compared to Veh female rats when assessed in a task widely validated to measure anxiety responses, the EPM (Figure 4), specifically based on the natural aversion for open and unsafe spaces (the open arms) and preference for closed and protected spaces (the closed arms of the maze). Behavior in this task is normally sex-dimorphic: female rats spend more time in open arms of EPM and exhibit head dipping more frequently than male rats, displaying lower anxiety levels [54][55][56][57][58][59]. Here we report that Pb exposure blunts sex dimorphism as Pb female rats show a marked reduction of time spent in the open arms, their behavior being similar to that observed in males in this same task.…”

Section: Discussionsupporting

confidence: 60%

Sex-Dependent Effects of Developmental Lead Exposure in Wistar Rats: Evidence from Behavioral and Molecular Correlates

Tartaglione

Serafini

Raggi

et al. 2020

IJMS

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Lead (Pb) exposure in early life affects brain development resulting in cognitive and behavioral deficits. Epidemiologic and experimental evidence of sex as an effect modifier of developmental Pb exposure is emerging. In the present study, we investigated Pb effects on behavior and mechanisms of neuroplasticity in the hippocampus and potential sex differences. To this aim, dams were exposed, from one month pre-mating to offspring weaning, to Pb via drinking water at 5 mg/kg body weight per day. In the offspring of both sexes, the longitudinal assessment of motor, emotional, and cognitive end points was performed. We also evaluated the expression and synaptic distribution of N-methyl-D-Aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits at post-natal day (pnd) 23 and 70 in the hippocampus. Neonatal motor patterns and explorative behavior in offspring were affected in both sexes. Pb effects in emotional response and memory retention were observed in adult females only, preceded by increased levels of GluN2A and GluA1 subunits at the post-synapse at pnd 23. These data suggest that Pb exposure during development affects glutamatergic receptors distribution at the post-synaptic spine in females. These effects may contribute to alterations in selected behavioral domains.

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“…One recent study in male and female rats illustrates this. 12 The results showed that females Only the future will tell us whether the semi-natural environment can offer more consistent data.…”

Section: Sex Difference In Immediate Fear Reactionsmentioning

confidence: 93%

“…6 Fear and anxiety-related behaviours are usually assessed through cation. [8][9][10][11][12] In the open field test, some data show that females cover more distance and display more rearing postures. 8,13 The proposal that females may show reduced fear in these procedures, whereas women are more at risk of developing mood disorder, is rather contradictory.…”

Section: Introductionmentioning

confidence: 99%

“…This ignores the fact that females sometimes display higher locomotor activity than males, regardless of the environmental context. 12,14,15 Motor activity is a potentially important confounding factor in measures of emotional status. 16 In addition, the above-mentioned classical tests suppress the social component of behaviour, despite its determining nature for highly social animals such as the rat.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Male and female immediate fear reaction to white noise in a semi‐natural environment: A detailed behavioural analysis of the role of sex and oestrogen receptors

Moëne

Ramírez-Rentería

Ågmo

2020

J Neuroendocrinology

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Sex differences in anxiety-like behaviors in rats

Cited by 172 publications

References 60 publications

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Sex-Dependent Effects of Developmental Lead Exposure in Wistar Rats: Evidence from Behavioral and Molecular Correlates

Male and female immediate fear reaction to white noise in a semi‐natural environment: A detailed behavioural analysis of the role of sex and oestrogen receptors

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