The Role Of Excitatory Signal Transmission Between MPFC And NAc In Impairment Of Motivational Behavior Associated With Chronic Pain

The prevalence of chronic pain is increasing worldwide which impacts both the lives of individuals and the functioning of society.A large number of studies have found that chronic pain not only impairs the physical functions,but also causes abnormalities in behavior,perception and cognitive functions of patients,which seriously affects their life and work.Fatigue,depression and other symptoms of abnormal motivational behavior are common in chronic pain patients.Understanding the underlying neural mechanism is critical for the development and implement of clinic treatments for motivation deficit.Previous studies have found that the medial prefrontal cortex(mPFC)and nucleus accumbens(NAc)are involved in abnormal motivational behavior associated with chronic pain.However,the role of the communication between the mPFC and the NAc in the change of motivational behavior under chronic pain is still unclear.Recent study of our lab showed that the communication between the mPFC and the NAc was weakened in the neuropathic animals with declined motivation.Thus,it is reasonable to hypothesize that the mPFC-NAc pathway plays a key role in the behavioral abnormalities associated with chronic pain.The main aims of this study were to firstly examine the role of signal transmission between the mPFC and the NAc in altering the motivational behavior in chronic pain state,and secondly to explore the underlying neural mechanism.To explore whether the mPFC-NAc pathway is involved in chronic pain-related motivational abnormalities,we examined the effect of changes in the activity of the mPFCNAc pathway on motivation-related behavior in neuropathic rats by selectively activating the pathway using optogenetic technique.Experiments were performed in a rat model of neuropathic pain with spared nerve injury(SNI).An effort-based decision-making task was used to determine level of motivation.The SNI rats showed lower motivation levels in the effort-based decision-making task.The decline was fully reversed by optogenetic activation of the mPFC-NAc pathway and the motivation reached pre-surgical level.The reversal effect of the optogenetic stimulation persisted one week after the cease of the stimulation.These results indicate that the decrease in signal transmission in the mPFCNAc pathway plays a key role in chronic pain-related motivational abnormalities,and upregulating the activity of this pathway can effectively improve the motivational disorders induced by chronic pain.We then conducted a series of in vitro electrophysiological analysis to further explore the cellular and synaptic mechanisms responsible for the inhibition of the mPFC-NAc pathway.Our results indicated that the electrophysiological characteristics of neurons in the mPFC and NAc underwent a series of changes in the neuropathologic pain state.Compared with Sham control group,the ability of mPFC neurons to transmit information through action potentials and the level of excitatory neurotransmitters released to the NAc were both significantly decreased in SNI animals.In addition,there was a significant reduction in the expression ratio of AMPAR/NMDAR on the postsynaptic membrane of NAc neurons which were synaptically connected with nerve terminals from mPFC neurons,while the proportion of calcium permeable AMPAR expression was increased.The recoding of synaptic currents evoked by stimulating mPFC projecting fibers showed a certain degree of long-term inhibition.These changes were more pronounced in the Dopamine receptor 2-type medium spiny neurons(D2-MSN).These findings suggest that the changes in synaptic transmission between mPFC and NAc neurons,through both preand post-synaptic mechanisms,may contitutes an important part of the mechanism for the decline in the efficiency of signal transmission in the mPFC-NAc pathway in chronic pain state.In summary,this study demonstrates that the plasticity of the mPFC-NAc pathway plays a key role in the change of motivational behavior in chronic pain state,providing important information for the understanding of the neural mechanisms of chronic painrelated motivational abnormalities.The demonstration of the efficacy of selective activation of mPFC-NAc pathway in improving motivational impairment in chronic pain animals offers an important scientific basis for the development of effective therapeutical interventions to treat motivational disorders related to chronic pain in humans.