Neural Circuitry And Molecular Swithers-Linking Emotions To The Modified Spatial Learning And Memory

[Background]Human beings have to face various emotion-associated stresses in pathyphysiological conditions.However,to the same stressful events,the attitudes of "hopefulness" or"hopelessness" can result in completely different behavioral and neurochemical consequences.To date,the neural circuits and the biological switchers that can link different emotions into the altered cognitive functions remain largely unknown.[Objective]To explore the neural circuits and the biological switchers that can link different emotions into the altered cognitive functions.[Methods]We report that unlike the inescapable foot shock(IFS,the well known model for learned hopelessness)that impair spatial reference learning and memory,the escapable avoidance training(EAT,known as learned hopefulness)during the aversive foot-shocks augments the spatial cognition in mice and rats.By FDG-PET scan,in circuitry c-Fos expression and living animal electrophysiological recording,we find that the foot-shocks with EAT remarkably enhances-the-functional and structural connections between posterior part of basolateral amygdale(BLP)and ventral hippocampal CA1(vCAl),while the hopelessly IFS weakens the BLP-vCAl circuit.Simultaneous blockage of BLP to vCA1 input by targeted AAV-NpHR expression at BLP and photostimulation at vCAl abolishes the beneficial effect of EAT,whereas activation of BLP-vCA1 circuit by AAV-ChR2 rescues the IFS-induced spatial memory deficits.Furthermore,optogenetic stimulation of BLP-vCA1 mimics the beneficial effect of EAT on spatial memory.Finally,we demonstrate that stimulating BLP-vCAl circuit by EAT or AAV-ChR2 increases synaptic transmission and dendritic plasticity with upregulation of CREB and intrasynaptic AMPA receptors in CA1,while blocking BLP-vCAl by IFS or AAV-NpHR impairs the synaptic plasticity.[Results]1.IFS impairs while EAT potentiates the hippocampus-dependent cognitive functions in muce.2.Opposite influence of LHL and LHF on BLP-vCAl circuit.3.Requirement,rescue and sufficiency of BLP-vCAl circuit in modifying the hippocampus-dependent spatial cognitive functions.4.Manipulating BLP-vCAl circuit modulates hippocampal synaptic plasticity with modifications of CREB and intrasynaptic AMPAR in CA1 subset.[Conclusion]Our findings indicate that switch-on or-off BLP-vCA1 excitatory monosynaptic input can modulate the hopefulness-and hopelessness-associated spatial learning and memory capacities,which reveal novel neural-circuit-specific mechanisms to link different emotions to the modified cognitive functions.[Background]Epidemiological studies indicate that mood disorders are common in early life,affecting approximately 2%to 8%of children and adolescents,respetively.Amongest mood disorders,depression is one of the most commonly seen.Currently,fluoxetine is the only selective serotonin reuptake inhibitor(SSRI)officially registered to treat major depressive disorder in children and.Adolescence is an important stage for brain development with cellular and molecular events such as neurogenesis,synaptogenesis and pruning.Although various pre-clinical studies have assessed the long-term effects of fluoxetine exposure in perinatal period and in the adulthood,limited data is available regarding the effects of the drup exposure on the developing brain later in life.With the growing prevalence of psychotropic drug prescriptions among children and adolescents,it is important to know whether the drug exposure during adolescent stage affect brain development and the cognitive functions in adulthood.[Objective]It was to explore whether and how a chronic fluoxetine exposure in adolescence affect the cognitive functions in adulthood.[Methods]Fluoxetine or the vehicle control was injected intraperitoneally into the male Sprague Dawley rats or mice at age of 35 postnatal days(PND)for 15 consecutive days.Then Morris Water maze and Barnes Maze test,BrdU and Golgi staining,ex-vivo electrophysiological recordings and Western blotting were performed.[Results]Fluoxetine administration during adolescent remarkably improved spatial memory ability of the rats measured in adults,whereas this effect was not observed when the drug was delieved in adulthood.Further studies showed that adolescent fluoxetine exposure facilitated survival of the newborn neurons with an augmented neurite arboration,dendrite generation and maturation in hippocampal CA1 and detate gyrus(DG)subsets.Simultaneously,the long term potentiation(LTP)of hippocampal SC-CA1 and PP-DG pathways was enhanced and postsynaptic biomarkers,including PSD95,GluRl and GluR2,increased after adolescent fluoxetine exposure.We also found that adolescent fluoxetine exposure significantly increased the protein level of TRPC1,while in the benificail effects of adolescent fluoxetine exposure on the neurogenesis and dendrite plasticity and as well as the spatial learning and memory were all abolished in TRPC1 knockout mice..[Conclusion]Fluoxetine exposure during adolescence facilitates spatial learning and memory,and the mechanisms involve TRPC1-associated neurogenesis and dendritic plasticity in hippocampus.[Background]Hippocampal neural circuits are important structural bases for memory.Recently more and more research indicates that,not only limited to cognition,hippocampus seems to be involved in many mental illnesses such as schizophrenia,severe depression and anxiety.Abnormal accumulation of microtubule-associated protein tau in hippocampal circuit is the early pathological changes of Alzheimer's disease(Alzheimer's Disease,AD)Meanwhile,hippocampal-dependent spatial-memory impairments and emotional changes form the early clinical features of Alzheimer's disease(AD).Hippocampal abnormal aggregation of tau proteins have been reported to be highly correlated with spatial memory impairment.[Objective]Thus,we hypothesize:tau protein may regulate memory and emotion via interfering hippocampal neural circuits and plays a key role in the development of memory and emotional disorders in AD.However,there is still little direct experimental evidence.[Methods]In this study,hippocampal CA3 stereotactic injection of virus expressing human full-length tau or mutated tau in adult mouse was applied.Then in vitro brain slice electrophysiological recordings and behavior tests were conducted on these mice.[Results]By in vitro brain slice electrophysiological recordings,we detected an impairment of hippocampal CA3-CA1 long-term potentiation(LTP),suggesting that tau expressed in CA3 disrupted the circuit function.Then we conducted animal behavioral test and found that the interference of tau in hippocampal circuit had resulted in spatial learning and memory deficits.More interestingly,abnormal expression of tau protein expression in CA3 induced anxiety-like behavioral in mice.[Conclusion]In short,these data provides direct experimental evidences that abnormal accumulation of tau leads to memory and emotional disorders through interfering hippocampal circuit.Our research establishes a novel animal model for the deep study of early diagnosis and treatment strategy for taupathies.Even more importantly,we demonstrate an important molecular target for explaining the integration of cognitive deficits and emotion disorders in neurodegenerative diseases.