GABAA receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat

Miller, Stephanie M.; Piasecki, Christopher C.; Peabody, Mitchell F.; Lonstein, Joseph S.

doi:10.1016/j.pbb.2010.03.007

Cited by 21 publications

(30 citation statements)

References 120 publications

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“…On the contrary, inhibition of GABA transmission in LS via microinfusion of GABAA receptor antagonist significantly disrupts offspring protection (also known as maternal aggression or maternal defense), while having no appreciable effect on other components of maternal behavior (Lee and Gammie, 2009), suggesting that elevated GABA in LS may promote maternal protective behavior. It should be noted that our findings of elevated postpartum GABA are consistent with GABA-mediated changes in maternal anxiety and offspring protection as increased GABA activity contributes to the attenuated postpartum anxiety and potentiated maternal defense (Lee and Gammie, 2009; Lonstein et al, 2014; Miller et al, 2010). Given that neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) have been intimately linked to maternal anxiety and defense (Bosch, 2011; Lonstein et al, 2014; Nephew and Bridges, 2008; Nephew et al, 2010), it would be interesting to know whether there are functional interactions between GABA, AVP and OXT in the control of maternal care and/or offspring protection.…”

Section: Discussionsupporting

confidence: 84%

Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period

Zhao

Gammie

2014

Brain Research

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Dramatic structural and functional remodeling occurs in the postpartum brain for the establishment of maternal care, which is essential for the growth and development of young offspring. Glutamate and GABA signaling are critically important in modulating multiple behavioral performances. Large scale signaling changes occur in the postpartum brain, but it is still not clear to what extent the neurotransmitters glutamate and GABA change and whether the ratio of glutamate/GABA remains balanced. In this study, we examined the glutamate/GABA-glutamine cycle in the lateral septum (LS) of postpartum female mice. In postpartum females (relative to virgins), tissue levels of glutamate and GABA were elevated in LS and increased mRNA was found for the respective enzymes producing glutamate and GABA, glutaminase (Gls) and glutamate decarboxylase 1 and 2 (Gad1 and Gad2). The common precursor, glutamine, was elevated as was the enzyme that produces it, glutamate-ammonia ligase (Glul). Additionally, glutamate, GABA, and glutamine were positively correlated and the glutamate/GABA ratio was almost identical in the postpartum and virgin females. Collectively, these findings indicate that glutamate and GABA signaling are increased and that the ratio of glutamate/GABA is well balanced in the maternal LS. The postpartum brain may provide a useful model system for understanding how glutamate and GABA are linked despite large signaling changes. Given that some mental health disorders, including depression and schizophrenia display dysregulated glutamate/GABA ratio, and there is increased vulnerability to mental disorders in mothers, it is possible that these postpartum disorders emerge when glutamate and GABA changes are not properly coordinated.

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Section: Discussionsupporting

confidence: 84%

Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period

Zhao

Gammie

2014

Brain Research

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“…However, the role of any of the given factors in contributing to gene expression changes can be evaluated in follow-up studies. Comparing lactating rodents to virgins has proven to be a valuable approach in past studies of maternal biology (Spinolo and Crowley, 1993; Miller et al, 2010; Jurek et al, 2012), and continuity in several consistent gene changes, such as Fabp7 , across studies that differ in species, brain region, and group housing conditions (Xiao et al, 2005) suggests that such an approach is able to successfully identify a robust maternal phenotype. We acknowledge that minor effects of housing-induced stress on gene expression cannot be excluded, but this experimental design optimally reduces the possibility of this effect manifesting differentially between groups and confounding results.…”

Section: Discussionmentioning

confidence: 99%

Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype

Eisinger

Driessen

Zhao

et al. 2014

Front. Behav. Neurosci.

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The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia and BPD.

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“…For example, lesion of the cPAGv decreases anxiety-related behavior in lactating rats [50], while infusion of a highly specific oxytocin receptor antagonist directly into the cPAGv increases anxiety in dams (as tested in the EPM) to the levels typically found in virgin females [51]. Infusion of bicuculline, a GABA A receptor antagonist in the cPAGv also significantly increases anxiety in dam rats [52]. It has been suggested that the pup-induced decrease in anxiety in mother rats might be mediated by the vBST and amygdala, as there was a higher Fos expression in the vBST in lower-anxiety mother rats (no pup separation) than higher-anxiety dams (whose pups were removed from them for 4 h before EPM testing) [53], and higher in the medial and cortical subregions of the amygdala in primiparous females tested with pups on the EPM than those tested without pups or to nulliparous females tested with or without pups [36], suggesting that these brain areas are involved in processing of pup cues.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and pharmacological investigation of anxiety and maternal responsiveness of postpartum female rats in a pup elevated plus maze

Qin

Chen

et al. 2015

Behavioural Brain Research

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The present study investigated the validity of a novel pup-based repeated elevated plus maze task to detect reduced anxiety and increased maternal responsiveness in postpartum female rats and explored the roles of dopamine D2, serotonin transporter and GABA/benzodiazepine receptors in the mediation of these processes. Sprague-Dawley postpartum or nulliparous female rats were tested 4 times every other day on postpartum days 4, 6 and 8 in an elevated plus maze with 4 pups or 4 pup-size erasers placed on each end of the two open arms. When tested with erasers, untreated postpartum mother rats entered the open arms proportionally more than nulliparous rats. They also tended to spend more time in the open arms, indicating reduced anxiety. When tested with pups, postpartum rats retrieved pups into the closed arms, entered the open arms and closed arms more and had a higher moving speed than nulliparous rats, indicating increased maternal responsiveness. Both haloperidol (0.1 or 0.2 mg/kg, sc) and fluoxetine (5 or 10 mg/kg, ip) dose- and time-dependently decreased the percentage of time spent in the open arms and speed, but did not affect the percentage of open arm entries. Diazepam (1.0 or 2.0 mg/kg, ip) did not affect pup retrieval, open arm time/entry in lactating rats. Thus, the percentage of open arm entries appears to be the most sensitive measure of anxiety in postpartum female rats, while speed could be used to index maternal responsiveness to pups, which are likely mediated by the dopamine D2 and serotonin transporter systems.

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GABAA receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat

Cited by 21 publications

References 120 publications

Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period

Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period

Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype

Behavioral and pharmacological investigation of anxiety and maternal responsiveness of postpartum female rats in a pup elevated plus maze

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