Npas4 deficiency increases vulnerability to juvenile stress in mice

Coutellier, Laurence; Gilbert, Valerie; Shepard, Ryan

doi:10.1016/j.bbr.2015.04.027

Cited by 26 publications

(31 citation statements)

References 54 publications

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“…However, it is unclear whether down-regulation of Npas4 is involved in the maladaptive changes that lead to stress-induced disorders or the stress adaption response that reinstates homeostasis. Results from studies using Npas4 knockout animals [32, 36], although not entirely consistent with each other, generally appear to support the latter idea, although mice deficient in Npas4 exhibited impaired adult neurogenesis in the hippocampal subventricular zone, consistent with the former possibility [32]. Further studies are needed to investigate Npas4’s function in stress in a region-specific manner, as it might play different roles in different brain regions.…”

Section: Behaviorally-induced Npas4 Expressionmentioning

confidence: 83%

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Npas4: Linking Neuronal Activity to Memory

Sun

Lin

2016

Trends in Neurosciences

162

146

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Immediate early genes (IEGs) are rapidly activated after sensory and behavioral experience and are believed to be critical for converting experience into long-term memory. Neuronal PAS domain protein 4 (Npas4), a recently discovered IEG, has several characteristics that make it likely to be a particularly important molecular link between neuronal activity and memory: it is among the most rapidly induced IEGs, is expressed only in neurons, and is selectively induced by neuronal activity. By orchestrating distinct activity-dependent gene programs in different neuronal populations, Npas4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity and memory formation. It may also be involved in circuit homeostasis through negative feedback and psychiatric disorders. We summarize these findings and discusses their implications.

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Section: Behaviorally-induced Npas4 Expressionmentioning

confidence: 83%

“…Treatment with corticosterone or physical stress exposure down-regulates Npas4 expression in both prefrontal cortex and hippocampus in vivo [21, 32–34]. This may result from the activation of glucocorticoid pathways that suppress Npas4 expression [35].…”

Section: Behaviorally-induced Npas4 Expressionmentioning

confidence: 99%

Npas4: Linking Neuronal Activity to Memory

Sun

Lin

2016

Trends in Neurosciences

162

146

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“…By regulating the number of inhibitory synapses onto excitatory cells, Npas4 is critical in limiting the amount of excitation that results from stimulation . In rodent models of decreased Npas4 expression, the resulting imbalance in cortical excitation leads to several disease‐relevant behavioral outcomes including: hyperactivity, seizures, social anxiety, contextual memory impairment and increased vulnerability to stress …”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] In rodent models of decreased Npas4 expression, the resulting imbalance in cortical excitation leads to several diseaserelevant behavioral outcomes including: hyperactivity, seizures, social anxiety, contextual memory impairment and increased vulnerability to stress. 14,[17][18][19][20] Among the environmental factors that are recognized as contributing to risk for neurodevelopment disorders, PNS is one of the most well established. PNS has been linked to several neuropsychiatric disorders, but the exact neural circuits and cellular mechanisms it alters during development, and the consequences of these alterations in later life have not yet been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Npas4 deficiency and prenatal stress interact to affect social recognition in mice

Heslin

Coutellier

2018

Genes Brain and Behavior

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Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia have an expansive array of reported genetic and environmental contributing factors. However, none of these factors alone can account for a substantial proportion of cases of either disorder. Instead, many gene-by-environment interactions are responsible for neurodevelopmental disturbances that lead to these disorders. The current experiment used heterozygous knock-out mice to examine a potential interaction between 2 factors commonly linked to neurodevelopmental disorders and cognitive deficit: imbalanced excitatory/inhibitory signaling in the cortex and prenatal stress (PNS) exposure. Both of these factors have been linked to disrupt GABAergic signaling in the prefrontal cortex (PFC), a common feature of neurodevelopmental disorders. The neuronal PAS domain protein 4 (Npas4) gene is instrumental in regulation of the excitatory/inhibitory balance in the cortex and hippocampus in response to activation. Npas4 heterozygous and wild-type male and female mice were exposed to either PNS or standard gestation, then evaluated during adulthood in social and anxiety behavioral measures. The combination of PNS and Npas4 deficiency in male mice impaired social recognition. This behavioral deficit was associated with decreased parvalbumin and cFos protein expression in the infralimbic region of the PFC following social stimulation in Npas4 heterozygous males. In contrast, females displayed fewer behavioral effects and molecular changes in PFC in response to PNS and decreased Npas4.

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“…Stress directly mediates NPAS4 activation, as agonist bound glucocorticoid receptor binds to the NPAS4 promoter to downregulate its expression during acute stress (Furukawa-Hibi et al, 2012). After chronic stress, NPAS4 mRNA is significantly decreased in the hippocampus of juvenile mice, and these NPAS4-deficient juveniles developed cognitive deficits in adulthood (Ibi et al, 2008; Yun et al, 2010; Coutellier et al, 2015). These long-term changes may arise through epigenetic regulation, as the NPAS4 promoter has several CpG islands, and stress increases methylation at these sites (Furukawa-Hibi et al, 2015).…”

Section: Npas4mentioning

confidence: 99%

Reward Network Immediate Early Gene Expression in Mood Disorders

Manning

Williams

Robison

2017

Front. Behav. Neurosci.

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Over the past three decades, it has become clear that aberrant function of the network of interconnected brain regions responsible for reward processing and motivated behavior underlies a variety of mood disorders, including depression and anxiety. It is also clear that stress-induced changes in reward network activity underlying both normal and pathological behavior also cause changes in gene expression. Here, we attempt to define the reward circuitry and explore the known and potential contributions of activity-dependent changes in gene expression within this circuitry to stress-induced changes in behavior related to mood disorders, and contrast some of these effects with those induced by exposure to drugs of abuse. We focus on a series of immediate early genes regulated by stress within this circuitry and their connections, both well-explored and relatively novel, to circuit function and subsequent reward-related behaviors. We conclude that IEGs play a crucial role in stress-dependent remodeling of reward circuitry, and that they may serve as inroads to the molecular, cellular, and circuit-level mechanisms of mood disorder etiology and treatment.

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Npas4 deficiency increases vulnerability to juvenile stress in mice

Cited by 26 publications

References 54 publications

Npas4: Linking Neuronal Activity to Memory

Npas4: Linking Neuronal Activity to Memory

Npas4 deficiency and prenatal stress interact to affect social recognition in mice

Reward Network Immediate Early Gene Expression in Mood Disorders

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