| Summary: |
Maintenance of hedonic homeostasis when faced with a sudden and persistent increase of high valence events,either pleasurable or aversive, is a critical function of the brain; disruption of this homeostasis leads to addictivevalence-seeking addictive behaviours or to valence-insensitive depressive behaviours (anhedonia). Interestingly,these seemingly opposite behaviours do not constitute the extreme ends of a spectrum because disruption ofemotional balance oft en results in the same profile: depressed individuals have high-prevalence of substance abusewhile substance abusers become avolitional to pursue non-addictive stimuli, while both show enhanced fearbehaviour [6]. However, the neural mechanisms of the interplay of depression and compulsion are still largelyunknown.
The most common clinical condition that disrupts hedonic processing is chronic pain; moreover, addiction andchronic pain share the same classic triad of characteristics of altered behaviour: impaired hedonic capacity,compulsion, and high stress/fear. Over the last decade, our research group has been at the forefront of preclinicalstudies of pain-induced malplasticity, and we have shown in a series of papers over the last 10 years, that changes inthe network of brain functional connectivity is an hallmark of chronic pain in animal models [1-5]. Usingsimultaneous multi-region neurophysiological recordings and optogenetic modulation, we have shown that chronicpain reduces the functional connectivity of prefrontal pathways, that this reduction in functional connectivityparallels the observed decrease in short term memory performance, that this disruption is largely dependent ondopaminergic signalling, and that optogenetic modulation of prefrontal neurons is able to rescue working-memory performance to normal levels [1-3,5]. More importantly, we have demonstrated the opposite eff ects in a transgenicmouse model of reduced pain perception, thus supporting our original working hypothesis [4]. Our resu  |
Summary
Maintenance of hedonic homeostasis when faced with a sudden and persistent increase of high valence events,either pleasurable or aversive, is a critical function of the brain; disruption of this homeostasis leads to addictivevalence-seeking addictive behaviours or to valence-insensitive depressive behaviours (anhedonia). Interestingly,these seemingly opposite behaviours do not constitute the extreme ends of a spectrum because disruption ofemotional balance oft en results in the same profile: depressed individuals have high-prevalence of substance abusewhile substance abusers become avolitional to pursue non-addictive stimuli, while both show enhanced fearbehaviour [6]. However, the neural mechanisms of the interplay of depression and compulsion are still largelyunknown.
The most common clinical condition that disrupts hedonic processing is chronic pain; moreover, addiction andchronic pain share the same classic triad of characteristics of altered behaviour: impaired hedonic capacity,compulsion, and high stress/fear. Over the last decade, our research group has been at the forefront of preclinicalstudies of pain-induced malplasticity, and we have shown in a series of papers over the last 10 years, that changes inthe network of brain functional connectivity is an hallmark of chronic pain in animal models [1-5]. Usingsimultaneous multi-region neurophysiological recordings and optogenetic modulation, we have shown that chronicpain reduces the functional connectivity of prefrontal pathways, that this reduction in functional connectivityparallels the observed decrease in short term memory performance, that this disruption is largely dependent ondopaminergic signalling, and that optogenetic modulation of prefrontal neurons is able to rescue working-memory performance to normal levels [1-3,5]. More importantly, we have demonstrated the opposite eff ects in a transgenicmouse model of reduced pain perception, thus supporting our original working hypothesis [4]. Our results also agreewith the hypothesis raised by whole brain imaging studies in pain patients that the sudden alteration in overallfunctional connectivity is the best objective neural correlate of chronic pain severity and that it has suff icientpredictive power to establish probability of pain chronification on an individual basis [7].
In the last few years, it has become increasingly clear that all brain areas involved in valence processing respond toboth pleasurable and aversive events, eff ectively blurring their functional separation. Midbrain ventrotegmental area,nucleus accumbens, prefrontal cortex, anterior cingulate, insula, amygdala, among others, simultaneously processevents of antagonical value and/or salience [8]. For this reason, many critical questions remain in our understandingof how prolonged aversive stimulation result in addictive behaviour and what are the neural mechanisms behind thismalplasticity: how are these neural pathways of dynamic reward/aversion processing aff ected during the loss ofhedonical homeostasis, like what occurs in prolonged pain? Are these changes in brain connectivity more prevalentin emotion-related areas of the brain, or are they simply a reflection of a decrease in functional connectivitythroughout the entire brain? And are sudden changes in rewarding/aversive episodes encoded as valence-relatedenhanced activity, or are the changes in hedonic balance encoded as new threshold setpoints for significant valence?And how do aversive conditions aff ect the transition from habits to addiction or from compulsive seek to compulsiveuse?
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