Dataset Information

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

ABSTRACT: Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions.

SUBMITTER: Hultman R

PROVIDER: S-EPMC4986697 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

Hultman Rainbo R Mague Stephen D SD Li Qiang Q Katz Brittany M BM Michel Nadine N Lin Lizhen L Wang Joyce J David Lisa K LK Blount Cameron C Chandy Rithi R Carlson David D Ulrich Kyle K Carin Lawrence L Dunson David D Kumar Sunil S Deisseroth Karl K Moore Scott D SD Dzirasa Kafui K

Neuron 20160623 2

Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and ...[more]

PMID: 27346529

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Project description:Epidemiological studies have shown that environmental insults and maternal stress during pregnancy increase the risk of several psychiatric disorders in the offspring. Converging lines of evidence from humans, as well as from rodent models, suggest that prenatal stress (PNS) interferes with fetal development, ultimately determining changes in brain maturation and function that may lead to the onset of neuropsychiatric disorders. From a molecular standpoint, transcriptional alterations are thought to play a major role in this context and may contribute to the behavioral phenotype by shifting the expression of genes related to excitatory and inhibitory (E/I) transmission balance. Nevertheless, the exact neurophysiological mechanisms underlying the enhanced vulnerability to psychopathology following PNS exposure are not well understood. In the present study, we used a model of maternal stress in rats to investigate the distal effects of PNS on the expression of genes related to glutamatergic and GABAergic neurotransmissions. We inspected two critical brain regions involved in emotion regulation, namely, the prefrontal cortex (PFC) and the amygdala (AMY), which we show to relate with the mild behavioral effects detected in adult rat offspring. We observed that PNS exposure promotes E/I imbalance in the PFC of adult males only, by dysregulating the expression of glutamatergic-related genes. Moreover, such an effect is accompanied by increased expression of the activity-dependent synaptic modulator gene Npas4 specifically in the PFC parvalbumin (PV)-positive interneurons, suggesting an altered regulation of synapse formation promoting higher PV-dependent inhibitory transmission and increased overall circuit inhibition in the PFC of males. In the AMY, PNS more evidently affects the transcription of GABAergic-related genes, shifting the balance toward inhibition. Collectively, our findings suggest that the E/I dysregulation of the PFC-to-AMY transmission may be a long-term signature of PNS and may contribute to increase the risk for mood disorder upon further stress.

Dataset Information

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

Publications

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

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