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Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD

View Article: PubMed Central - PubMed

ABSTRACT

It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD). What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a “stuck accelerator.” Interestingly, increasing evidence demonstrates that dopamine (DA) – traditionally known for its role in motivation, reward prediction, and addiction – is also crucial in regulating fear learning and anxiety. Yet, how dopaminergic (DAergic) neurons control stress resilience is unclear, especially given that DAergic neurons have multiple subtypes with distinct temporal dynamics. Here, we propose the Rebound-Excitation Theory, which posits that DAergic neurons’ rebound-excitation at the termination of fearful experiences serves as an important “brake” by providing intrinsic safety-signals to fear-processing neural circuits in a spatially and temporally controlled manner. We discuss how DAergic neuron rebound-excitation may be regulated by genetics and experiences, and how such physiological properties may be used as a brain-activity biomarker to predict and confer individual resilience to stress and anxiety.

No MeSH data available.


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Representative amygdalar fear circuits (blue) with DA circuit (red) involvement. DA units showing rebound-excitation to two distinct types of fearful stimuli: free fall (top) and earthquake (bottom). Rebound-excitation occurs at the termination of fearful stimuli and is proposed to serve as an innate safety signal to modulate fear-related learning and behaviors by broadcasting to downstream targets such as the amygdala (Amy), nucleus accumbens (NAc), prefrontal cortex (PFC), or hippocampus (Hipp).
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Figure 1: Representative amygdalar fear circuits (blue) with DA circuit (red) involvement. DA units showing rebound-excitation to two distinct types of fearful stimuli: free fall (top) and earthquake (bottom). Rebound-excitation occurs at the termination of fearful stimuli and is proposed to serve as an innate safety signal to modulate fear-related learning and behaviors by broadcasting to downstream targets such as the amygdala (Amy), nucleus accumbens (NAc), prefrontal cortex (PFC), or hippocampus (Hipp).

Mentions: To specifically examine how DAergic neurons respond to traumatic fear in real-life events, we used laboratory versions of fearful unconditioned stimuli (US) (such as an earthquake, free fall, or foot-shocks) that induce profound fear memory and rapid cardiac responses in freely behaving mice (63). Combined with pharmacological and optogenetic methods, chronic in vivo recordings of VTA DAergic neural activities in freely behaving mice have shown two major types of DAergic neuron responses: fear-inhibited and fear-excited DAergic neurons (40). Notably, we observed that many aversive-inhibited DAergic neurons show phasic rebound-excitation responses at the offset of unexpected aversive stimuli (40) (Figure 1). This unique response pattern to fearful US has lent us the idea that offset phasic rebound-excitation of this particular sub-population of DAergic neurons may act as a critical safety signal to encode the termination of a fearful event. The signal strength of this phasic DA release, time-locked to the termination of fearful events, will exert immediate as well as long-term changes in downstream targets, thereby setting up the different thresholds for each individual’s resilience to stress and anxiety.


Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD
Representative amygdalar fear circuits (blue) with DA circuit (red) involvement. DA units showing rebound-excitation to two distinct types of fearful stimuli: free fall (top) and earthquake (bottom). Rebound-excitation occurs at the termination of fearful stimuli and is proposed to serve as an innate safety signal to modulate fear-related learning and behaviors by broadcasting to downstream targets such as the amygdala (Amy), nucleus accumbens (NAc), prefrontal cortex (PFC), or hippocampus (Hipp).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037223&req=5

Figure 1: Representative amygdalar fear circuits (blue) with DA circuit (red) involvement. DA units showing rebound-excitation to two distinct types of fearful stimuli: free fall (top) and earthquake (bottom). Rebound-excitation occurs at the termination of fearful stimuli and is proposed to serve as an innate safety signal to modulate fear-related learning and behaviors by broadcasting to downstream targets such as the amygdala (Amy), nucleus accumbens (NAc), prefrontal cortex (PFC), or hippocampus (Hipp).
Mentions: To specifically examine how DAergic neurons respond to traumatic fear in real-life events, we used laboratory versions of fearful unconditioned stimuli (US) (such as an earthquake, free fall, or foot-shocks) that induce profound fear memory and rapid cardiac responses in freely behaving mice (63). Combined with pharmacological and optogenetic methods, chronic in vivo recordings of VTA DAergic neural activities in freely behaving mice have shown two major types of DAergic neuron responses: fear-inhibited and fear-excited DAergic neurons (40). Notably, we observed that many aversive-inhibited DAergic neurons show phasic rebound-excitation responses at the offset of unexpected aversive stimuli (40) (Figure 1). This unique response pattern to fearful US has lent us the idea that offset phasic rebound-excitation of this particular sub-population of DAergic neurons may act as a critical safety signal to encode the termination of a fearful event. The signal strength of this phasic DA release, time-locked to the termination of fearful events, will exert immediate as well as long-term changes in downstream targets, thereby setting up the different thresholds for each individual’s resilience to stress and anxiety.

View Article: PubMed Central - PubMed

ABSTRACT

It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD). What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a “stuck accelerator.” Interestingly, increasing evidence demonstrates that dopamine (DA) – traditionally known for its role in motivation, reward prediction, and addiction – is also crucial in regulating fear learning and anxiety. Yet, how dopaminergic (DAergic) neurons control stress resilience is unclear, especially given that DAergic neurons have multiple subtypes with distinct temporal dynamics. Here, we propose the Rebound-Excitation Theory, which posits that DAergic neurons’ rebound-excitation at the termination of fearful experiences serves as an important “brake” by providing intrinsic safety-signals to fear-processing neural circuits in a spatially and temporally controlled manner. We discuss how DAergic neuron rebound-excitation may be regulated by genetics and experiences, and how such physiological properties may be used as a brain-activity biomarker to predict and confer individual resilience to stress and anxiety.

No MeSH data available.


Related in: MedlinePlus