Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats

Darling, Ryan D.; Alzghoul, Loai; Zhang, Junlin; Khatri, Nidhi; Paul, Ian A.; Simpson, Kate; Lin, Rick C.S.

doi:10.1523/jneurosci.3736-11.2011

Cited by 28 publications

(22 citation statements)

References 49 publications

(87 reference statements)

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“…It should be noted that observed deficits after early exposure to CTM seen only in males were reported in other studies after similar drug applications (20,45,46). For example, it has been shown that impaired social behavior and response to novelty are more obvious in CTM-exposed male compared with female rats (20).…”

Section: Discussionmentioning

confidence: 50%

“…For example, it has been shown that impaired social behavior and response to novelty are more obvious in CTM-exposed male compared with female rats (20). Drug exposure also selectively alters both spontaneous and stimulus-driven activity of LC neurons in male rather than female rats (45). All of these results suggest a sexually dimorphic response in our CTM-exposed rodent model.…”

Section: Discussionmentioning

confidence: 57%

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Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Zhou

Darling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drugexposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1-10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticitybased therapeutics in autistic patients.autism | behavioral training | cortical network | antidepressant exposure | recovery of function R ecently, extensive efforts have been made to understand better the etiology of pervasive developmental disorders (PDDs), such as autism spectrum disorders (ASDs), with an ultimate goal of identifying preventive and more effective treatment strategies. At present, a general consensus from both human and animal studies is that a variety of genetic and environmental factors play an integrated role in the establishment of neurobehavioral abnormalities marking these disorders (1-5). Given the complexity of its origins and of the expressions of neurological abnormalities in ASD, it has been generally concluded that no single drug or therapy can be expected to provide effective treatment for the core and associated symptoms of ASDs (6-9).Interestingly, early behavioral intervention has been associated with significant improvements in intelligence quotient, language acquisition, and adaptive behavior (10). Furthermore, positive outcomes of individuals with an unequivocal history of moderate-severe ASD (11) provide hope that the strong behavioral deficits expressed in the disorder might, on some corrective neurobehavioral path, be reversible. What is that path? A critical question to answer is whether and to what extent the cortical network dysfunction and the subcortical machinery that regulates it, repeatedly described as distorted in humans with autism and in animal models of autism (12-15), can be reversed, either through drug treatment or via behavioral approaches.Cortical circuit mi...

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 57%

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Zhou

Darling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Structural dimorphism in the rat LC has also been observed, though the direction of effect depends on the strain of rat (compare Babstock et al, 1997; Bangasser et al, 2011; and Luque et al, 1992). Finally, postnatal citalopram exposure in rats causes ectopic projection of LC fibers into the neocortex and increased LC excitability in males, but not females (Darling et al, 2011). We expand upon this body of research by identifying thousands of genes expressed in the LC and sex differences therein, as well as recurrent, conserved motifs in cis with these genes.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

et al. 2018

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SUMMARY Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females—which we leverage to illustrate the behavioral and pharmacologic relevance of these findings—and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.

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“…In a mature brain, acute SRI exposure may have an inverse modulatory effect whereby it upregulates 5HT and downregulates norepinephrine-locus coeruleus (NE-LC) (17). In a rodent model, Maciag et al (14) reported downregulated 5HT-raphe circuit function following citalopram exposure during a period analogous to the human third trimester, whereas enhanced NE-LC system function has been reported following neonatal citalopram administration (18). Such early (or fetal) exposure leading to increased locus ceruleus (NE-LC) function raises an intriguing question of whether anxious childhood behavior in exposed children may also reflect abnormal noradrenergic (NE) transmission (19).…”

Section: Discussionmentioning

confidence: 99%

Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior

2015

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Background: Animal research has suggested that prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure causes increased anxiety-like behaviors in adulthood. We examined whether in utero SRI exposure influenced externalizing and internalizing behaviors in children at 3 y and again at 6 y of age. Methods: We recruited women in their second trimester of pregnancy from primary maternity care providers in Vancouver British Columbia, Canada. We compared the internalizing, externalizing, and the anxious and attention subscales of the internalizing behaviors scores of children exposed to SRIs and children not exposed to SRIs at age 3 and age 6. results: We included 110 mother-child pairs (44 exposed to SRI and 66 not exposed). Higher levels of internalizing and anxious behaviors were reported in SRI exposed children at both 3 and 6 y of age compared with children who were not exposed (F = 7.52, P = 0.0072 and F = 7.91, P = 0.0058, respectively). The fully adjusted hierarchical regression models indicated a positive and significant relationship between SRI exposure and increased internalizing and anxious behaviors even when controlling for maternal mood during pregnancy, postpartum and childhood. conclusion: SRI exposure was associated with sustained higher levels of internalizing behaviors in early childhood even when controlling for maternal depression.

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Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats

Cited by 28 publications

References 49 publications

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior

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