Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress

Kumar, Sunil; Hultman, Rainbo; Hughes, Duncan B.; Michel, Nadine; Katz, Brittany M.; Dzirasa, Kafui

doi:10.1038/ncomms5537

Cited by 115 publications

(117 citation statements)

References 49 publications

(79 reference statements)

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“…In addition to the NAc, several other brain regions have also been implicated in susceptibility to SDS, including the medial frontal cortex (mFC) (28,29) and the amygdala (Amyg) (30). Interestingly, Tph2KI mice have previously been reported to exhibit aberrant connectivity between the mFC and the Amyg (31).…”

Section: Resultsmentioning

confidence: 99%

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Sachs¹,

Ni²,

Caron

2015

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

100

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Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression-and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLXinsensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.serotonin | stress | antidepressants | habenula S tress is thought to play a key role in the development of neuropsychiatric disorders, but only a small percentage of individuals exposed to stress develop mental illnesses. To account for this, diathesis-stress hypotheses of neuropsychiatric disorders postulate that stress only leads to maladaptive behavior and psychiatric disease in individuals who harbor certain vulnerability factors (or diatheses) (1-3). However, the diatheses that lead to increased susceptibility to psychosocial stress remain largely unknown.Levels of brain serotonin (5-HT) have long been implicated in the development and treatment of neuropsychiatric disorders. Indeed, biomarkers of 5-HT deficiency have been identified in subpopulations of depression patients (4), and mutations within 5-HT-system genes have been associated with affective disorders, anxiety disorders, and alterations in stress sensitivity (3,(5)(6)(7)(8). In addition, most antidepressant drugs increase extracellular levels of brain 5-HT. However, whether brain 5-HT deficiency alters stress susceptibility or contributes to the development of aberrant emotional behavior remains largely unresolved. Here we examined the consequences of low levels of brai...

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Section: Resultsmentioning

confidence: 99%

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Sachs¹,

Ni²,

Caron

2015

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

100

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“…Anatomical 3D volumetric images were converted to MINC format, and were registered iteratively: (i) to a reference image using 6 degrees of freedom (df) transform, (ii) by 12 df affine transformation between each pair of individual images, and (iii) with 3 consecutive non-linear transformations between each pair of images, using MICe-build-model and ANTS (Lerch et al, 2008). Region of interest analysis was performed using a set of ROIs derived from the Allen mouse brain atlas (http://www.mouse.brain-map.org) adapted to MRI space.…”

Section: Data Processingmentioning

confidence: 99%

“…Therefore, it will be important to build on the present evidence for increased between-network FC involving the amygdala in CPS mice in terms of understanding the changes in the excitation-inhibition between these networks. Interestingly, in CSD mice, an electrophysiology study also demonstrated increased coherence between the neuronal firing signals obtained from PFC and amygdala (Kumar et al, 2014). In human FC studies, the amygdala has been studied mainly in the affective network, depression-related changes in which remain to be investigated (Dutta et al, 2014).…”

Section: Increases In Within-and Between-network Functional Connectivmentioning

confidence: 99%

“…For example, chronic social defeat (CSD) (Golden et al, 2011) leads to social avoidance and decreased interest in gustatory reward (Covington et al, 2009;Krishnan et al, 2007). In vivo electrophysiology has provided evidence for altered PFC -amygdala coherence in terms of neuronal firing in CSD mice (Kumar et al, 2014). Ex vivo structural MRI identified correlations between CSD-induced social avoidance and the volumes of several sub-cortical brain regions (Anacker et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

et al. 2016

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Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala -prefrontal cortex and amygdala -cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry. AbstractHuman depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward.Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a posttreatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in b...

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“…Further work by the Dzirasa laboratory has also shown that naturally occurring differences in corticolimbic synchrony correlates with trait vulnerability to CSDS, with greater phase locking between the PFC and amygdala predicting increased vulnerability. 163 Interestingly, as mentioned above, animal and human studies have shown that 5-HT is a major regulator of vmPFC-amygdala coupling and reducing 5-HT using genetic mouse models of 5-HT deficiency or pharmacological treatments has been shown to favor cortico-amygdala hypersynchrony and enhance vulnerability to social defeat (Figure 5). 164 …”

Section: Social-experience-induced Structural and Functional Plasticimentioning

confidence: 96%

Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression

Challis

Berton

2015

ACS Chem. Neurosci.

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Social withdrawal, increased threat perception and exaggerated reassurance seeking behaviors are prominent interpersonal symptoms in major depressive disorder (MDD). Altered serotonin (5-HT) systems and corticolimbic dysconnectivity have long been suspected to contribute to these symptomatic facets, however, the underlying circuits and intrinsic cellular mechanisms that control 5-HT output during socioemotional interactions remain poorly understood. We review literature that implicates a direct pathway between the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN) in the adaptive and pathological control of social approach-avoidance behaviors. Imaging and neuromodulation during approach-avoidance tasks in humans point to the cortical control of brainstem circuits as an essential regulator of socioemotional decisions and actions. Parallel rodent studies using viral-based connectomics and optogenetics are beginning to provide a cellular blueprint of the underlying circuitry. In these studies, manipulations of vmPFC synaptic inputs to the DRN have revealed bidirectional influences on socioaffective behaviors via direct monosynaptic excitation and indirect disynaptic inhibition of 5-HT neurons. Additionally, adverse social experiences that result in permanent avoidance biases, such as social defeat, drive long-lasting plasticity in this microcircuit, potentiating the indirect inhibition of 5-HT output. Conversely, neuromodulation of the vmPFC via deep brain stimulation (DBS) attenuates avoidance biases by restoring the direct excitatory drive of 5-HT neurons and strengthening a key subset of forebrain 5-HT projections. Better understanding the cellular organization of the vmPFC-DRN pathway and identifying molecular determinants of its neuroplasticity can open fundamentally novel avenues for the treatment of affective disorders.

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Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress

Cited by 115 publications

References 49 publications

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression

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