Alzheimer's disease (AD) is characterized by the presence of senile plaques. The core of the plaque consists of beta-amyloid protein. In AD patients, learning and memory are impaired with a concomitant loss of the cholinergic marker enzyme, choline acetyltransferase (ChAT). However, direct evidence that beta-amyloid protein is related to the impairment of learning and memory has not been demonstrated. In this study, we investigated whether memory impairment and neuronal dysfunction were produced after 2 weeks continuous infusion of beta-amyloid protein (3, 30 and 300 pmol/day) into the cerebral ventricles in adult rats. To investigate the ability of learning and memory in beta-amyloid protein-treated rats, water maze and passive avoidance tasks were carried out. The performance of both tasks in beta-amyloid protein-treated rats was impaired. ChAT activity in the frontal cortex (3 and 30 pmol/day) and hippocampus (300 pmol/day) significantly decreased. These results suggest that beta-amyloid protein is related to the impairment of learning and memory, and neurodegeneration, and that beta-amyloid protein-treated rats could be used as an animal model for AD.
Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. In our well-established mouse models of methamphetamine (Meth) self-administration and reinstatement, bilateral microinjection of adeno-associated virus vectors expressing GDNF (AAV-Gdnf) into the striatum significantly reduced Meth self-administration, without affecting locomotor activity. Moreover, the intrastriatal AAV-Gdnf attenuated cue-induced reinstatement of Meth-seeking behaviour in a sustainable manner. In addition, this manipulation showed that Meth-primed reinstatement of Meth-seeking behaviour was reduced. These findings suggest that the AAV vector-mediated Gdnf gene transfer into the striatum is an effective and sustainable approach to attenuate Meth self-administration and Meth-associated cue-induced relapsing behaviour and that the AAV-mediated Gdnf gene transfer in the brain may be a valuable gene therapy against drug dependence and protracted relapse in clinical settings.
Cannabis withdrawal syndrome (CWS) in humans is characterized by various somatic symptoms, including sleep disturbances. In the present study, we investigated sleep alterations in mice after the cessation of arachidonylcyclopropylamide (ACPA), a cannabinoid type 1 receptor agonist, administration. ACPA-administered mice (ACPA mice) displayed an increased number of rearings after the cessation of ACPA administration compared to saline-administered mice (Saline mice). Moreover, the number of rubbings was also decreased in ACPA mice compared with those of the control mice. Electroencephalography (EEG) and electromyography (EMG) were measured for 3 days after the cessation of ACPA administration. During ACPA administration, there was no difference in the relative amounts of total sleep and wake time between ACPA and Saline mice. However, ACPA-induced withdrawal decreased total sleep time during the light period in ACPA mice after ACPA cessation. These results suggest that ACPA cessation induces sleep disturbances in the mouse model of CWS.
Abstract In recent years, the number of patients with depression disorders has increased. New stratagem should be established for the recovery of depression. The gene encoding Teneurin-4 (Tenm-4), ODZ4, has been identified as a risk gene for many psychiatric disorders1,2,3. However, it is still unclear how Tenm-4 affects the pathogenesis of psychiatric disorders. Prefrontal cortex (PFC) contributes emotion regulation, cognitive function, and social behaviors4,5. Importantly, a reduced volume of the PFC region has been reported in depressed patients6. Therefore, the PFC is thought to be involved in the pathogenesis of depression. We hypothesized that Tenm-4 in the PFC influences depression and other psychiatric disorders. In this study, we generated mice with Tenm-4 knockdown specifically in the PFC of mice, to clarify the involvement of Tenm-4 in psychiatric disorders in the PFC, We investigated their behavioral phenotype by conducting various behavioral experiments. Mice with reduced Tenm-4 expression in the PFC were generated using genetic modification technology incorporating the CRISPER- Cas9 system in an adeno-associated virus vector (AAV)(Tenm-4 KD, and Mock as control), and we used these mice for the behavioral experiments. We performed various behavioral experiments by using the mice. In the forced swimming test and tail suspension test, Tenm-4 KD mice group showed significantly increased immobility time compared with Mock mice group. In the sucrose preference test, Tenm-4 KD mice group showed significantly decreased sucrose preference compared with Mock mice group. Furthermore, a single intraperitoneal dose of aripiprazole significantly decreased immobility time in the tail suspension test and restored sucrose preference in the sucrose preference test in mice accompanied with reducion Tenm-4 expression. These results suggest that reduction of Tenm-4 in the PFC would cause depression-like behaviors. Further, we revealed that depression-like behaviors induced by reduction of the Tenm-4 in the PFC was recovered by the administration of aripiprazole. Aripiprazole functions as a partial agonist of dopamine D2,3 receptors, a partial agonist of serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2Areceptors. Therefore, this result suggests that the dopaminergic and/or Serotonergic neurons, especially in the PFC, would be involved in depression-like behaviors induced by reduction of the Tenm-4 in the PFC. The relationship between depression and Tenm-4 is still not well understood. However, we have successfully generated a new mouse model of depression induced by decreased Tenm-4 in the PFC. These results could provide a pathomechanism involving Tenm-4 in depression. Our study successfully identified a new therapeutic target for depressed patients. References 1.Yi, X., Li, M., He, G., Du, H., Li, X., Cao, D., Wang, L., Wu, X., Yang, F., Chen, X., He, L., Ping, Y., &Zhou, D. (2021). Genetic and functional analysis reveals TENM4 contributes to schizophrenia. iScience, 24. doi: 10.1016/j.isci.2021.103063 2.Xue, B, C., Xu, H, Z., Zhu, J., Wu, Y., Zhuang, H, X., Chen, L, Q., Wu, R, C., Hu, T, J., Zhou, S, H., Xie, H, W., Yi, X., Yu, S, S., Peng, Y, Z., Yang, M, H., Hong, H, X.,& Chen, H, J. (2019). Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21. Front Genet, 9.doi: 10.3389/fgene.2018.00725 3.Psychiatric GWAS Consortium Bipolar Disorder Working Group. (2011). Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet, 43, 977-983. doi: 10.1038/ng.943 4.Hiser, J., &Koenigs, M. (2018). The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology. Biol Psychiatry, 83, 638-647. doi: 10.1016/j.biopsych.2017.10.030 5.Merre, L, P., Ä hrlund-Richter, S., &Carlé n, M. (2021). The mouse prefrontal cortex: Unity in diversity. Neuron, 109, 1925-1944. doi: 10.1016/j.neuron.2021.03.035 6.Schmaal, L. Hibar, P, D., Sä mann, G, P., Hall, B, G., Baune, T, B., Jahanshad, N., Cheung, J, W., Erp, G, M van, T., Bos, D., Ikram, A, M., Vernooij, N., Niessen, J, W., Tiemeir, H. Hofman, A., Wittfeld, K., Grabe, J, H., Janowitz, D., Bü low, R., Selonke, M., Vö lzke, M., Grotegerd, D., Dannlowski, U., Arolt, V., Opel, N., Heindel, W., Kugel, H., Hoehn, D., Czisch, M., Couvy-Duchesene, B., Renterí a, E, M., Strike, T, L., Wright, J, M., Mills, T, N., Zubicaray, I de, G., McMahon, L, K., Medlamd, E, S., Martin, G, N., Gillespie, A, N., Goya- Maldonado, R., Grubar, O., Krä mer B., Hatton, N, S., Lagopoulos, L., Hickie, B, I., Frodl, T., Carballedo, A., Frey, M, E., Velzen, S van, L., Penninx, W, J, H, B., Tol van M-J., Wee, J van der, N., Davey, G, C., Harrison, J, B., Mwangi, B., Cao, B., Soares, C, J., Veer, M, I., Walter, H., Schopef, D., Zurowski, B., Konrad, C., Schramm, E., Normann, C., Schnell, K., Sacchet, D, M., Gotlib, H, I., MacQueen, M, G., Godlewska, R, B., Nickson, T., Mclntosh, D, M., Papmeyer, M., Whalley, C, H., Hall, J., Sussmann, E, J., Li, M., Walter, M., Aftanas, L., Brack, I., Bokhan, A, N., Thompson, M, P., Veltmen, J, D. (2017). Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry, 22, 900-909. doi: 10.1038/mp.2016.60
Neuronal atrophy or death occurs in aging and neurological diseases. Recent research has identified some neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6, and their involvement in various processes in neuronal growth, differentiation, and maintenance has been clarified (Leibrock et al., 1989; Hohn et al., 1990; Maisonpierre et al., 1990; Hallbook et al., 1991; Gotz et al., 1994). These neurotrophins are closely linked to injured cells and are capable of initiating a cascade of events in neurons and glia designed to prevent further damage. In many types of injury, both in the central nervous system (CNS) and in the peripheral nervous system (PNS), the induction of neurotrophins has been observed. The amounts of NGF increase after sciatic nerve lesion or transection (Lindholm et al., 1987), fimbria fornix transection (Gasser et al., 1986; Weskamp et al., 1986), electrolytic lesion of the septohippocampal pathway (Hefti, 1986; Oderfeld-Nowak et al., 1992), needle injection (Ballarin et al., 1991), denervation of the nigral dopaminernergic neuronal system (Nitta et al., 1992), limbic seizures (Gall and Issackson, 1989), transection of the optic nerve (Lu et al., 1991), excitotoxic destruction of hippocampal neurons (Bakhit et al., 1991), bilateral decortication (Lorez et al., 1988), and the evocation of aggressive behavior in adult male mice (Spillantini et al., 1989).
Background: Shati/Nat8l significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment.We reported that the expression of Shati/Nat8l mRNA was increased following brain development in mice, while there was a reduction in the myelin basic protein (MBP) level in the prefrontal cortex of juvenile, but not adult, Shat/Nat8l knockout (Shati KO) mice.We found Shati KO mice demonstrates induces several behavioral deficits.Furthermore we also reported Shati/Nat8l affects neuronal axon outgrowth in the primary mice cultured neurons.Previous findings have suggested that Shati/Nat8l has essential roles in neuronal function.In this study, we carried out various behavioral and electrophysiological study using Shati KO mice to clarify the contribution of Shati/Nat8l on the cognitive function in mice.Methods: We assessed the validity of behavioral test using Shati KO mice and wild type (WT) mice such as open field test, social interaction test, elevated plus maze test, Y-maze test and novel object recognition test.Next, hippocampal slices were prepared from Shati KO and WT mice, and recorded the evoked field excitatory postsynaptic potentials and longterm potentiation (LTP) using MED64 systems.Results: In the open field test, Shati KO mice showed higher basal locomotor activity.Shati KO mice avoided social interaction with unfamiliar mice compared with WT mice.In the elevated plus maze test, Shati KO mice spent much longer time in open arms than WT mice.These behavioral changes were observed both male and female Shati KO mice.Interestingly, inpairment of cognitive dysfunction in the Y-maze and novel object recognition were observed only in Shati KO female mice.Furthermore, injection of adeno associated virus vector of Shati/Nat8l into hippocampal CA3 region of Shati KO ameliorated these cognitive dysfunctions in the female mice.Also in the electrophysiology test, the LTP of Shati KO mice were significantly decreased compared with wild type mice of both male and female mice.Conclusions: These results suggest that Shati/Nat8L would be associated with cognitive function of mice and the impairment has some sexual differences. Poster session WCP2018
