Behavioral effects of SGK1 knockout in VTA and dopamine neurons

Doyle, Marie; Stark, Ali; Fejes-Tóth, Géza; Náray-Fejes-Tóth, Anikó; Mazei-Robison, Michelle S.

doi:10.1038/s41598-020-71681-9

Cited by 5 publications

(3 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…absence of floxed target sequences). Using littermate controls without the floxed gene, but not differentiating between full WT and heterozygous DAT-Cre carriers as controls, as has been done in studies using this strain [60][61][62][63][64] , as well as with the DAT IRES-cre strain [65][66][67][68][69][70][71] , might mislead interpretations of experimental results.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

Costa

Schenkel

Roeper

2021

Sci Rep

View full text Add to dashboard Cite

Heterozygous mice that express Cre-recombinase under the dopamine transporter promoter (DAT-Cre knock in mice, or KI) are widely used for targeting midbrain dopamine neurons, under the assumption that their constitutive physiology is not affected. We report here that these mice display striking sex-dependent behavioral and molecular differences in relation to wildtypes (WT). Male and female KI mice were constitutively hyperactive, and male KI mice showed attenuated hyperlocomotor responses to amphetamine. In contrast, female KIs displayed a marked reduction in locomotion (“calming” effect) in response to the same dose of amphetamine. Furthermore, male and female DAT-Cre KI mice showed opposing differences in reinforcement learning, with females showing faster conditioning and males showing slower extinction. Other behavioral variables, including working memory and novelty preference, were not changed compared to WT. These effects were paralleled by differences in striatal DAT expression that disproportionately affected female KI mice. Our findings reveal clear limitations of the DAT-Cre line that must be considered when using this model.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

Costa

Schenkel

Roeper

2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The primer sequences for SGK1 and β-actin were: SGK1: 5′-ATCGTGTTAGCTCCAAAGC-3′, 5′-GTCTGTGATCAGGCATAGC-3′. 37 β-actin: 5′-CCCTAAGGCCAACCGTGAA-3′, 5′-AGAGGCATACAGGGACAACACA-3′.…”

Section: Methodsmentioning

confidence: 99%

The role of serum/glucocorticoid-regulated kinase 1 in brain function following cerebral ischemia

Wu,

Zhang,

et al. 2024

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Cardiopulmonary arrest (CA) is a major cause of death/disability in the U.S. with poor prognosis and survival rates. Current therapeutic challenges are physiologically complex because they involve hypoperfusion (decreased cerebral blood flow), neuroinflammation, and mitochondrial dysfunction. We previously discovered novel serum/glucocorticoid-regulated kinase 1 (SGK1) is highly expressed in brain of neurons that are susceptible to ischemia (hippocampus and cortex). We inhibited SGK1 and utilized pharmacological (specific inhibitor, GSK650394) and neuron-specific genetic approaches (shRNA) in rodent models of CA to determine if SGK1 is responsible for hypoperfusion, neuroinflammation, mitochondrial dysfunctional, and neurological deficits after CA. Inhibition of SGK1 alleviated cortical hypoperfusion and neuroinflammation (via Iba1, GFAP, and cytokine array). Treatment with GSK650394 enhanced mitochondrial function (via Seahorse respirometry) in the hippocampus 3 and 7 days after CA. Neuronal injury (via MAP2, dMBP, and Golgi staining) in the hippocampus and cortex was observed 7 days after CA but ameliorated with SGK1-shRNA. Moreover, SGK1 mediated neuronal injury by regulating the Ndrg1-SOX10 axis. Finally, animals subjected to CA exhibited learning/memory, motor, and anxiety deficits after CA, whereas SGK1 inhibition via SGK1-shRNA improved neurocognitive function. The present study suggests the fundamental roles of SGK1 in brain circulation and neuronal survival/death in cerebral ischemia-related diseases.

show abstract

“…Cre-recombinase (Cre) gene expression was used to confirm viral targeting of the BNST. All samples were run in triplicate and normalized to Gapdh before analysis using the ΔΔCt method (Doyle et al, 2020).…”

Section: Qpcr -Bnst Grin2d Knockdown Validationmentioning

confidence: 99%

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

Doyle,

Salimando,

Altemus

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh+ neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh+ neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naive female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

show abstract

Behavioral effects of SGK1 knockout in VTA and dopamine neurons

Cited by 5 publications

References 62 publications

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

The role of serum/glucocorticoid-regulated kinase 1 in brain function following cerebral ischemia

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

Contact Info

Product

Resources

About