PET Based Molecular Imaging Research On Fear Circuity

Over the past decades,with the continuous deterioration of the natural environment,disharmony between man and nature increases.As a result,natural disasters occur frequently.Disasters not only deprive people’s lives,but also cause severe trauma and pain both physically and mentally.In the face of a disaster,most people develop a series of adaptive response;however,a few people will suffer from stress related mental disorders,such as post-traumatic stress disorder(PTSD)and anxiety disorders.At present,the available therapeutic drugs for PTSD and anxiety disorders don’t successfully relieve clinical symptoms in all patients.A growing number of evidence suggest that cognitive behavior therapy(CBT)is a more efficient approach than drug therapy for the treatment of PTSD.However,the underlying neural mechanisms have not been fully elucidated.Exposure therapy shares similar neurobiological mechanisms with fear extinction in animal models.To investigate the neurobiological mechanisms of PTSD and exposure-based therapy,we performed fluorodeoxyglucose([18F]FDG)small animal positron emission tomography(microPET)imaging to study the regional brain glucose metabolism change during fear conditioning and extinction retrieval in rats.In addition,we assessed brain metabolism changes during contextual conditioning and contextual retrieval in a rat model of anxiety,to unravel the neural responses associated with symptoms of anxiety.Part 1:PET imaging of fear conditioning and extinction in a rat model of post-traumatic stress disorderObjective:The aim of this study was to assess brain metabolism changes and neuroactivity during fear conditioning and extinction retrieval,to map memory engrams in a rat model of PTSD.Methods:Serial[18F]FDG microPET imaging studies were performed after tone presentation,fear conditioning or extinction retrieval phase,respectively.In parallel,immunohistological studies were conducted to assess the expression of neuroactivity marker c-Fos protein.Results:During fear conditioning,increased[18F]FDG accumulation was found in the bilateral amygdale,but decreased in the bilateral secondary motor cortex(M2),left primary somatosensory cortex(S1)and left ventroposterior medial(VPM)nucleus of the thalamus compared with tone presentation phase(P<0.001).During extinction(?)retrieval,increased[18F]FDG accumulation was found in the right primary visual cortex and right posterior insular cortex,but decreased in a cluster comprising the right orbital cortex,lateral septum and bilateral bed nucleus of the stria terminalis(BNST)compared with the tone presentation phase(P<0.001).Immunohistological studies demonstrated increased c-Fos expression in the posterior insular cortex after extinction retrieval(P<0.01).Conclusion:Our results support a key role for the amygdala in fear memory formation.The PET imaging findings combined with immunohistological data provide compelling evidence that the posterior insular cortex is involved in the retrieval of extinction memory.PET imaging of fear circuitry in animal models may provide a valuable translational approach to better characterize pathophysiological mechanisms of PTSD.Part 2:PET imaging of contextual fear in a rat model of anxiety disordersObjective:The aim of this study was to assess brain metabolism changes during contextual conditioning and contextual retrieval,to map memory engrams in a rat model of anxiety disorders.Methods:Serial[18F]FDG microPET imaging studies were performed during baseline,contextual conditioning or contextual retrieval,respectively.Results:During contextual conditioniig,increased[18F]FDG accumulation was found in the bilateral ventral hippocampus(vHPC),anterior cingulate cortex(ACC)and olfactory bulb,but decreased in the bilateral primary motor cortex(M1),right S1,cerebellum and right visual cortex(P<0.001).During contextual retrieval,increased[18F]FDG accumulation was found in the bilateral vHPC,ACC,left amygdala and olfactory bulb,but decreased in the bilateral S1,secondary somatosensory cortex(S2),simple lobule of cerebellum and bilateral posterior thalamic nuclei(P<0.001).Conclusion:The current results extend our understanding of anxiety by showing that a widely distributed network of interconnected brain regions,including the ACC,vHPC and amygdala,acts together to dynamically modulates anxiety states.PET imaging of anxiety circuitry in animal models serves as a means to not only understand the neurocircuitry involved but also aid in the diagnosis and prediction of treatment responses of anxiety disorders.Future studies are required to develop a more detailed understanding of the distributed neural circuits that support the expression of normal and pathological anxiety.