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

Hultman, Rainbo; Mague, Stephen D.; Li, Qiang; Katz, Brittany M.; Michel, Nadine; Lin, Lizhen; Wang, Joyce; David, Lisa K.; Blount, Cameron; Chandy, Rithi; Carlson, David; Ulrich, Kyle; Carin, Lawrence; Dunson, David B.; Kumar, Sunil; Deisseroth, Karl; Moore, Scott D.; Dzirasa, Kafui

doi:10.1016/j.neuron.2016.05.038

Cited by 114 publications

(131 citation statements)

References 49 publications

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“…3C), such that the amount of immobility exhibited by mice during the second session was lower than expected based on their IL-Thal CFPC. Consistent with the observations that direct PFC stimulation induces an anti-depressant like effect in multiple MDD-related test paradigms (6, 23), these findings suggested that IL-Thal CFPC may reflect a neurophysiological process that induces TST movement. When we used our nCLASP system to recapitulate the spatiotemporal dynamic we identified in IL-Thal circuitry, our findings confirmed that IL-Thal CFPC induces TST-related movement.…”

Section: Discussionsupporting

confidence: 86%

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

Carlson

David

Gallagher

et al. 2017

Biological Psychiatry

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Background The prefrontal cortex (PFC) plays a critical role in regulating emotional behaviors, and dysfunction of PFC-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder (MDD). Methods Here we acquire multi-circuit in vivo activity from eight cortical and limbic brain regions as mice are subjected to the tail suspension test (TST) and an open field test (OFT). We use a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and OFT. We then perform repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. Results The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex (IL) and medial dorsal thalamic (Thal), and an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using “closed-loop” optogenetic stimulation is sufficient to increase movement in the TST in stress-naïve mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in IL-Thal circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. Conclusion Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.

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Section: Discussionsupporting

confidence: 86%

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

Carlson

David

Gallagher

et al. 2017

Biological Psychiatry

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“…This is similar to a report that even a single episode of stress can weaken functional connectivity between the two areas measured by resting state fMRI (Liang et al, 2014). Indeed, such stress-induced disruptions in prefrontal-to-amygdala connectivity is also known to affect social interaction and anxiety-related behaviors in rodents (Adhikari et al, 2015;Hultman et al, 2016). Finally, it is interesting to note that the same chronic stress paradigm was previously shown to strengthen functional connectivity from the amygdala to the hippocampus (Ghosh et al, 2013), which undergoes stress-induced deficits similar to the mPFC (Arnsten, 2015;Chattarji et al, 2015;McEwen and Morrison, 2013).…”

Section: Resultssupporting

confidence: 88%

Extinction recall of fear memories formed before stress is not affected despite amygdalar hyperactivity

Chattarji

Rahman

Shukla

2018

Preprint

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Stress is known to exert its detrimental effects not only by enhancing fear, but also by impairing its extinction. However, in earlier studies stress exposure invariably preceded both processes. Thus, compared to unstressed animals, stressed animals had to extinguish fear memories from higher levels of freezing caused by prior exposure to stress. Here we decouple the two processes to examine if stress specifically impairs fear extinction.Strikingly, when fear memories were formed before stress exposure, thereby allowing animals to initiate extinction from comparable levels of fear, recall of fear extinction was unaffected. Despite this we observed a persistent increase in theta activity in the BLA.Theta activity in the mPFC, by contrast, was normal. Stress also disrupted mPFC-BLA theta-frequency synchrony and directional coupling. Thus, in the absence of the fearenhancing effects of stress, the expression of fear reflects normal regulation of mPFC activity, not stress-induced hyperactivity in the amygdala.

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“…We then sought to determine whether the same ACC→BLA circuit was involved in a more ethologically-relevant task – the avoidance of aggressive and potentially threatening animals (Hultman et al, 2016). Naïve observer mice were injected with NpHR or eYFP bilaterally in the ACC and implanted with optical fibers over the BLA, and the ACC→BLA projection was inhibited while the observer witnessed the interaction of a familiar demonstrator mouse and an aggressive CD-1 mouse for two 3-minute sessions (Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning

Allsop

Wichmann

Mills

et al. 2018

Cell

238

206

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Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT.

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

Cited by 114 publications

References 49 publications

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

Extinction recall of fear memories formed before stress is not affected despite amygdalar hyperactivity

Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning

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