Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor

Graybeal, Carolyn; Kiselycznyk, Carly; Holmes, Andrew

doi:10.1016/j.neuroscience.2012.02.042

Cited by 25 publications

(17 citation statements)

References 159 publications

(167 reference statements)

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“…Results of our study provide evidence that the loss of one allele of the regulatory subunit of PKA is associated with increased PKA activity in the amygdala and importantly no change in PKA activity in the orbitofrontal cortex between threat conditions, as seen in WT littermates. Our results are congruent with other studies, which note that dysfunction in OFC – amygdala neural pathways are associated with atypical behavioral response to threat detection and subsequent increased vulnerability to development of psychopathology (Arnsten and Rubia, 2012; Yuen et al, 2012; Graybeal et al, 2012; Arnsten, 2009). Our findings suggest that increased PKA signaling in Prkar1a +/- mice is associated with anxiety and hyperarousal symptoms and failure to extinguish fear response (Blanchard et al, 1979; Kalin et al, 2004).…”

Section: Discussionsupporting

confidence: 92%

Threat bias in mice with inactivating mutations of Prkar1a

et al. 2013

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Anxiety disorders are associated with abnormalities in the neural processing of threat-related stimuli. However, the neurobiological mechanisms underlying threat bias in anxiety are not well understood. We recently reported that a Prkar1a heterozygote (Prkar1a+/-) mouse with haploinsufficiency for the main regulatory subunit (R1α) of protein kinase A (PKA) exhibits an anxiety-like phenotype associated with increased cAMP signaling in the amygdala. Prkar1a+/- mice provide a novel model to test the direct effect of altered PKA expression and subsequent anxiety-like behavioral phenotype on the response to threat. We hypothesized that Prkar1a+/-mice would exhibit a bias in threat detection since increased amygdala activity during emotional stimuli is associated with a maladaptive response. We measured behavior and PKA activity in brain areas after exposure to predator or control odor exposure in male Prkar1a+/- and wild-type (WT) littermates. Indeed, there were significant differences in the behavioral response to threat detection; WT mice showed the expected response of decrease in exploratory behavior during predator vs. control odor exposure, while Prkar1a+/- mice did not alter their behavior between conditions. Basal and total PKA activity was independently associated with genotype, with an interaction between genotype and threat condition. Prkar1a+/- mice had higher PKA activity in amygdala and ventromedial hypothalamus in response to predator odor. In contrast, WT mice had higher PKA activity in amygdala and orbitofrontal cortex after exposure to control odor. Dysregulated PKA activity in the amygdala- prefrontal cortex circuitry in Prkar1a+/- mice is associated with behavioral phenotype of anxiety and a bias for threat. This is likely related to a failure to inhibit the amydgala response, which is an effect of the genotype. These results suggest that the alteration in PKA signaling in Prkar1a+/- mice is not ubiquitous in the brain; tissue-specific effects of the cAMP/PKA pathway are related to threat detection and fear sensitization.

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Section: Discussionsupporting

confidence: 92%

Threat bias in mice with inactivating mutations of Prkar1a

et al. 2013

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“…Other studies had already demonstrated the effects of chronic stress on the morphology of pyramidal neurons, such as structural modifications on dendritic arborization and decrease in the number of dendritic spines [18,20], probably due to an increase in the number of excitatory amino acids (glutamate) induced by greater amounts of glucocorticoids in the bloodstream [50,56,63]. Chronic stress also increased the expression of genes that regulate neuronal metabolism and synaptic changes in glutamate receptors [10,73]. In addition to excitatory neurons, inhibitory neurons are also vulnerable to the effects of chronic stress.…”

Section: Discussionmentioning

confidence: 96%

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Folha

Bahia

Aguiar

et al. 2017

Behavioural Brain Research

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h i g h l i g h t s• Chronic stress impairs the development of the adolescent brain.• Chronic stress delays the maturation of extracellular structures called perineuronal nets, which stabilize synaptic contacts on inhibitory neurons, and prefrontal cortex-associated behavior.• These negative effects of chronic stress on the prefrontal cortex can theoretically occur in humans. Critical periods of plasticity (CPPs) are defined by developmental intervals wherein neuronal circuits are most susceptible to environmental influences. The CPP of the prefrontal cortex (PFC), which controls executive functions, extends up to early adulthood and, like other cortical areas, reflects the maturation of perineuronal nets (PNNs) surrounding the cell bodies of specialized inhibitory interneurons. The aim of the present work was to evaluate the effect of chronic stress on both structure and function of the adolescent's rat PFC. We subjected P28 rats to stressful situations for 7, 15 and 35 days and evaluated the spatial distribution of histochemically-labeled PNNs in both the Medial Prefrontal Cortex (MPFC) and the Orbitofrontal Cortex (OFC) and PFC-associated behavior as well. Chronic stress affects PFC development, slowing PNN maturation in both the (MPFC) and (OFC) while negatively affecting functions associated with these areas. We speculate upon the risks of prolonged exposure to stressful environments in human adolescents and the possibility of stunted development of executive functions.

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“…Chronic stress also has detrimental effects on many behaviors. For instance, several studies have demonstrated stress-induced deficits on a variety of cognitive tasks, including fear conditioning and retrieval of extinction, attentional set-shifting, spatial learning and recognition, and working memory [reviewed in 10, 11–13]. However, it is not well understood how stress acts on the brain to contribute to the development of psychopathology.…”

Section: Chronic Stress Psychopathology and Corticolimbic Structmentioning

confidence: 99%

Sex differences and chronic stress effects on the neural circuitry underlying fear conditioning and extinction

Farrell

Sengelaub

Wellman

2013

Physiology & Behavior

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There are sex differences in the rates of many stress-sensitive psychological disorders such as post traumatic stress disorder (PTSD). As medial prefrontal cortex and amygdala are implicated in many of these disorders, understanding differential stress effects in these regions may shed light on the mechanisms underlying sex-dependent expression of disorders like depression and anxiety. Prefrontal cortex and amygdala are key regions in the neural circuitry underlying fear conditioning and extinction, which thus has emerged as a useful model of stress influences on the neural circuitry underlying regulation of emotional behavior. This review outlines the current literature on sex differences and stress effects on dendritic morphology within medial prefrontal cortex and basolateral amygdala. Such structural differences and/or alterations can have important effects on fear conditioning and extinction, behaviors that are mediated by the basolateral amygdala and prefrontal cortex, respectively. Given the importance of extinction-based exposure therapy as a treatment for anxiety disorders such as PTSD, understanding the neural mechanisms by which stress differentially influences fear learning and extinction in males and females is an important goal for developing sex-appropriate interventions for stress-related disorders.

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Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor

Cited by 25 publications

References 159 publications

Threat bias in mice with inactivating mutations of Prkar1a

Threat bias in mice with inactivating mutations of Prkar1a

Effect of chronic stress during adolescence in prefrontal cortex structure and function

Sex differences and chronic stress effects on the neural circuitry underlying fear conditioning and extinction

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