Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

Rebello, Tahilia J.; Yu, Qinghui; Goodfellow, Nathalie M.; Cagliostro, Martha K. Caffrey; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y.; Chemiakine, Alexei; Rosoklija, Gorazd; Dwork, Andrew J.; Lambe, Evelyn K.; Gingrich, Jay A.; Ansorge, Mark S.

doi:10.1523/jneurosci.1020-13.2014

Cited by 120 publications

(191 citation statements)

References 99 publications

(3 reference statements)

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“…2E)-a measure of behavioral despair in rodents used to screen for antidepressants (51,52). These findings replicate previous results of early-life FLX treatment (48,53) and are comparable with those obtained after infant trauma, as modeled by paired odor-shock conditioning (Fig. 3C) (12) or rearing with an abusive mother (13,19).…”

Section: Infant Trauma Induces Preference Learning Of Trauma Cues Andsupporting

confidence: 87%

“…2D) associated with later-life depressive-like behavior ( Fig. 3 A and C), providing insight into possible mechanisms by which early-life FLX treatment produces detrimental effects (46,48,53,58). These data demonstrate that 5-HT is developmentally sensitive to infant experiences and that alterations in 5-HT during critical periods in early life can be a predisposing factor for later-life affective dysfunction (41-43, 47, 57).…”

Section: Discussionmentioning

confidence: 76%

“…Early postnatal life constitutes a critical period during which alterations in 5-HT impact adult emotional behavior, suggesting that 5-HT plays a key role in the development of brain circuits that modulate adult emotionality (43)(44)(45)(46)(47). Indeed, atypical infant increases in 5-HT induced by chronic fluoxetine (FLX) exposure, 5-HT transporter knockout, or disruptions in maternal care, result in long-term changes in 5-HT and contribute to later-life depression-like symptoms (11,(44)(45)(46)48). Third, learned safety signals exert protective effects on animal models of depression comparable with those obtained by adult antidepressant treatment (36), suggesting that serotonergic mechanisms contribute to these repair effects.…”

Section: Significancementioning

confidence: 99%

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Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Rincón-Cortés

Barr

Mouly

et al. 2015

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

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Children form a strong attachment to their caregiver-even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues-a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.E arly-life trauma is associated with compromised neurobehavioral development and vulnerability to later-life psychiatric disorders like depression (1-5). Long-lasting effects of infant trauma relevant to depression include disruptions in social behavior, alterations in the serotonin (5-HT) system, and amygdala dysfunction (2, 5-8), which have been replicated by animal models (9-15). Paradoxically, trauma-linked cues-even those associated with abusive attachment-can elicit strong attraction and feelings of comfort in humans (16,17). Furthermore, a lifelong attraction to trauma-linked cues has also been demonstrated in rodent models of infant trauma, which suggests that sensory cues learned during infancy alter adult behaviors and amygdala activity (12,18,19).To explore the enduring effects of infant trauma and the mechanisms underlying their modulation by infant trauma-linked cues, we used an odor-learning paradigm during the sensitive period for attachment learning in rat pups, postnatal (PN) days 8-12, which is characterized by rapid and robust odor-preference learning that extends to aversive stimuli (14,(20)(21)(22). Specifically, we used infant olfactory classical conditioning in which a novel peppermint odor is paired with a mild shock (0.5 mA, 1s) to produce a preferred odor that functions behaviorally as a maternal odor and results in neural activation comparable with that induced by natural maternal odor (20,(23)(24)(25). During the sensitive period, low endogenous levels of corticosterone (CORT) and attenuated shock-induced CORT release prevent the infant amygdala from exhibiting the learning-induced plasticity required for avoidance learning (1...

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Section: Infant Trauma Induces Preference Learning Of Trauma Cues Andsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 76%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Rincón-Cortés

Barr

Mouly

et al. 2015

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

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“…In support of this idea, the probability of observing a ChR2-EPSC onto 5-HT neurons was much lower (∼14%; i.e., 11 of 76 recordings) when the ChR2 virus was injected in superficial subregions of the mPFC (i.e., cingulate and prelimbic regions) compared with when injections were directed to the deeper infralimbic region of the mPFC (76%; i.e., 419 of 545 recordings). Intriguingly, lesions of the infralimbic regions of the PFC, but not of the prelimbic regions, lead to the appearance of anxiety-related traits in mice (31). Future work will determine whether these moodrelated changes are mediated by a compromised top-down control from these deep layers of the PFC to the DRN subnetwork.…”

Section: Discussionmentioning

confidence: 96%

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Geddes

Assadzada

Lemelin

et al. 2016

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

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Serotonin (5-HT) neurons located in the raphe nuclei modulate a wide range of behaviors by means of an expansive innervation pattern. In turn, the raphe receives a vast array of synaptic inputs, and a remaining challenge lies in understanding how these individual inputs are organized, processed, and modulated in this nucleus to contribute ultimately to the core coding features of 5-HT neurons. The details of the long-range, top-down control exerted by the medial prefrontal cortex (mPFC) in the dorsal raphe nucleus (DRN) are of particular interest, in part, because of its purported role in stress processing and mood regulation. Here, we found that the mPFC provides a direct monosynaptic, glutamatergic drive to both DRN 5-HT and GABA neurons and that this architecture was conducive to a robust feed-forward inhibition. Remarkably, activation of cannabinoid (CB) receptors differentially modulated the mPFC inputs onto these cell types in the DRN, in effect regulating the synaptic excitatory/inhibitory balance governing the excitability of 5-HT neurons. Thus, the CB system dynamically reconfigures the processing features of the DRN, a mood-related circuit believed to provide a concerted and distributed regulation of the excitability of large ensembles of brain networks.optogenetics | synapse | glutamate receptors | anxiety | depression T he phylogenetically old neurotransmitter serotonin (5-HT) is known to regulate a remarkably wide range of brain functions and behaviors, such as mood, aggression, reward, perception, levels of arousal, and decision making (1-5). The 5-HT-containing neurons are localized in a collection of small brainstem nuclei collectively known as the raphe nuclei, with the largest being the dorsal raphe nucleus (DRN). These neurons send extensive and widespread axonal projections throughout the forebrain (6). As such, the firing of a relatively small number of 5-HT neurons is powerfully poised to regulate the excitability of large ensembles of neural networks distributed across virtually the entire brain. However, little is known about how the synaptic networks impinging onto the DRN regulate the excitability of its constituent cells to generate the core feature selectivity of 5-HT neurons and, ultimately, to regulate the dynamic output of 5-HT to the brain. A significant step forward in this direction has recently been achieved by a number of anatomical studies that provide a comprehensive list of the brain regions projecting to the DRN, as well as detailed cartography of the connectivity patterns of these inputs to local cellular elements within the DRN subnetwork (i.e., 5-HT neurons, local GABAergic neurons) (7-9). The top-down control exerted by the phylogenetically recent medial prefrontal cortex (mPFC) over the DRN is of particular importance, in part, because of the purported role of this pathway in regulating several aspects of motivation and stress processing, and in mediating antidepressant-like effects (1, 10, 11). The mechanistic details of this long-range connectivity are elusive, howe...

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“…For example, animals administered SSRIs or 5-HTT blocking tricyclic antidepressants during the first 3 weeks of postnatal life (P4-P21), but not in adulthood (P90-P107 or P56-P70), mimic the prodepressive and anxiogenic phenotype observed in transgenic models with constitutively enhanced 5-HTergic tone (Ansorge et al, 2004(Ansorge et al, , 2008Popa et al, 2008). We have recently refined this SSRI-sensitive period to P2-P11, and extended the behavioral characterization, finding impaired hippocampal-dependent spatial learning and contextual fear learning, as well as diminished amygdala and PFCdependent fear extinction and extinction recall (Rebello et al, 2014). This P2-P11 period, interestingly, not only lies within the maturation period of both 5-HTergic afferents and cortical circuits (Kiyasova and Gaspar, 2011b;Lidov and Molliver, 1982a;Lidov and Molliver, 1982a;Vitalis et al, 2013), but also coincides with the peak of cortical 5-HT and 5-HT metabolite levels (Hohmann et al, 1988; Figure 1).…”

Section: -Ht and Emotional And Cognitive Behaviormentioning

confidence: 88%

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

Suri

Teixeira

Cagliostro

et al. 2014

Neuropsychopharmacol

142

125

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Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system development, such sensitive periods shape the formation of neurocircuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint as well as the environmental context. While allowing for adaptation, such sensitive periods are also vulnerability windows during which external and internal factors can confer risk to disorders by derailing otherwise resilient developmental programs. Here we review developmental periods that are sensitive to monoamine signaling and impact adult behaviors of relevance to psychiatry. Specifically, we review (1) a serotonin-sensitive period that impacts sensory system development, (2) a serotonin-sensitive period that impacts cognition, anxiety-and depressionrelated behaviors, and (3) a dopamine-and serotonin-sensitive period affecting aggression, impulsivity and behavioral response to psychostimulants. We discuss preclinical data to provide mechanistic insight, as well as epidemiological and clinical data to point out translational relevance. The field of translational developmental neuroscience has progressed exponentially providing solid conceptual advances and unprecedented mechanistic insight. With such knowledge at hand and important methodological innovation ongoing, the field is poised for breakthroughs elucidating the developmental origins of neuropsychiatric disorders, and thus understanding pathophysiology. Such knowledge of sensitive periods that determine the developmental trajectory of complex behaviors is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders.

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Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

Cited by 120 publications

References 99 publications

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

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