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P.1.j.005 Infliximab rescues cognitive impairment induced by unpredictable chronic mild stress in a rat model of depression
P.1.j. Basic and clinical neuroscience − Cognitive neuroscience P.1.j.003 Diffusion tensor imaging in posttraumatic patients: the role of the corpus-callosum in PTSD symptomatology and memory impairments R. Saar-Ashkenazy1 ° , J. Guez2 , Y. Jacob3 , R. Vexler4 , I. Shelef5 , H. Shalev6 , A. Friedman1 , J. Cohen7 1 Ben Gurion University of the Negev, Cognitive Neuro-science, Beer-Sheva, Israel; 2 Achva Academic College, Psychology, Beer-Tuvia, Israel; 3 Tel Aviv University, Wohl Institute for Advanced Imaging, Tel-Aviv, Israel; 4 Ben Gurion University of the Negev, Physiology and Cell Biology, Beer-Sheva, Israel; 5 Soroka University Medical Center, Radiology, Beer-Sheva, Israel; 6 Soroka University Medical Center, Psychiatry, Beer-Sheva, Israel; 7 Hadassah Medical Organization, Sharett Institute of Oncology, Beer-Sheva, Israel Several neuroimaging studies in PTSD have revealed structural differences in specific gray-matter regions (e.g. anterior cingulate cortex, hippocampus and the amygdala) with smaller cortical volumes frequently reported in traumatic patients. Recently, whitematter alterations have become a target for extensive research in post-traumatic stress disorder (PTSD), with a recent review concluding that overall, reductions in white-matter volume were more often reported than increases [1]. While these studies show promise for further characterization of PTSD-related abnormalities, most critical in these studies is the absence of evidence for clinical correlates between PTSD symptomatology and cognitive measures and the reported imaging results. The aim of the current study was to examine to what extent white-matter integrity is associated with symptomatology and memory in PTSD. 16 PTSD patients and 14 matched-control subjects participated in the study. PTSD symptoms severity was assessed via the clinician-administrated PTSD scale (CAPS). Based on our previous results [2], the corpus-callosum (CC) was defined as a region of interest. All fiber tracking was performed by DtiStudio (H. Jiang, S. Mori; Johns-Hopkins University). Memory performance was measured by an associative-deficit index (ADI) based on an item-association memory paradigm. CC white-matter integrity indicator (fractional-anisotropy, FA) was significantly correlated to PTSD symptoms (i.e. total CAPS score, anterior: r = −0.559, p = 0.047, mid-anterior: r = −0.669, p = 0.009, central: r = −0.767, p = 0.001, mid-posterior: r = −0.669, p = 0.009, a trend was found with the posterior portion: r = −0.486, p = 0.092). Significant correlations in the PTSD group were found between the ADI in the words task and the CC FA values of the mid-posterior (r = −0.641, p = 0.046) and posterior (r = −0.679, p = 0.044) portions as well as the total CC (r = −0.645, p = 0.044). RT in the associative pictorial task was highly correlated to FA values of the anterior (r = −0.657, p = 0.039) and central (r = −0.667, p = 0.035) portions as well as to the total CC (r = −0.648, p = 0.043). The correlation analysis indicated that white-matter alterations are not uniformly observed in PTSD patients. To confirm this, we divided the PTSD group into 2 sub-groups: severe and not-sever PTSD (severe PTSD was determined by a CAPS score >80 [3]) and compared the CC FA values between groups. The results revealed a significant difference between groups in all CC-compared portions (z = −2.266 p = 0.023, z = −2.666 p = 0.007, z = −2.666 p = 0.007, z = −2.533 p = 0.01, z = −2.133 p = 0.032 and z = −2.933 p = 0.003 for the anterior, mid-anterior, central, midposterior, posterior and total CC, respectively). Comparing high symptomatic patients with control subjects resultant in significant decreased FA values in patients (z = −2.677 p = 0.007, z = −1.984
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p = 0.047 and z = −2.299 p = 0.021 for the mid-anterior and anterior CC portions, as well as the total CC, respectively), and a significant difference between groups in the RT of the associative pictorial task (z=2.051, p = 0.040). The current study demonstrated an association between both PTSD symptomatology and memory performance and whitematter integrity. We suggest that altered inter-hemispheric whitematter connectivity is a pathophysiological mechanism contributing to PTSD symptoms and memory deficits observed in this population. References [1] Daniels, J.K., Lamke, J.P., Gaebler, M., Walter, H., & Scheel, M. (2013). White matter integrity and its relationship to ptsd and childhood trauma--a systematic review and meta-analysis. Depress Anxiety, 30(3), 207–216. [2] Saar-Ashkenazy, R., Cohen, J., C., G., J., G., I., S., A., F., & H., S. (2014). Reduced Corpus-Callosum Volume in Posttraumatic Stress Disorder Highlights the Importance of Interhemispheric Connectivity for Associative Memory. The Journal of Traumatic Stress, 27(1), 18−26. [3] Weathers, F.W., Keane, T.M., & Davidson, J.R. (2001). Clinicianadministered PTSD scale: a review of the first ten years of research. Depress Anxiety, 13(3), 132–156.
P.1.j.005 Infliximab rescues cognitive impairment induced by unpredictable chronic mild stress in a rat model of depression T. Demirtas1 ° , T. Utkan1 , Y. Yazir2 , A. Karson3 , F. Balci4 , D. Bayramgurler5 1 Kocaeli University Medical School, Pharmacology, Izmit-Kocaeli, Turkey; 2 Kocaeli University Medical School, Histology and Embriyology, Izmit-Kocaeli, Turkey; 3 Kocaeli University Medical School, Physiology, IzmitKocaeli, Turkey; 4 Ko¸c University, Psychology, Istanbul, Turkey; 5 Kocaeli University Medical School, Dermatology, Izmit-Kocaeli, Turkey Purpose: Many depressed patients showed increased levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-a) in the clinic. Furthermore, anti-depressant compounds have anti-inflammatory effects in both depressed patients and animal models of depression. Unpredictable chronic mild stress (UCMS) is a valuable animal model of depression. We have recently reported that infliximab (a TNF-a inhibitor) decreased anhedonia and despair-like behavior in the rat chronic mild stress model of depression [1]. Increasing number of evidence also points at a relation between inflammation and cognitive impairments. The aim of this study was to investigate the effect of infliximab on UCMS-induced cognitive impairments in rats. Methods: Animals were divided into three groups (n = 12 per group): Control, UCMS and UCMS+infliximab. Control and UCMS groups received physiological saline, UCMS+infliximab group received infliximab during 8 weeks of UCMS. Infliximab was injected intraperitoneally once a week at a dose of 5 mg/kg. Briefly, UCMS and UCMS+infliximab groups were subjected to different types of stressors: Restraint for 4 h, cage tilting for 24 h, wet bedding for 24 h, swimming in 4ºC cold water for 5 min, swimming in 45ºC hot water for 5 min, pairing with another stressed animal for 48 h, level shaking for 10 min, and inversion of the light/dark cycle for 24 h. The stressors were randomly applied for 56 days and each stressor was applied 4−5 times during this time period. To determine the effects of UCMS and infliximab
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treatment on cognitive functions; locomotor activity (LA), passive avoidance (PA) and Morris water maze (MWM) tests were used. Hippocampal brain-derived neurotrophic factor (BDNF) levels of rats were evaluated immunohistochemically. Experimental results were analyzed with one-way and two-way ANOVA, post hoc Bonferroni test and Kruskal–Wallis test. Results: There were no significant differences between three groups in terms of LA (p = 0.28). In the PA test, therewas no significant difference between the first day latency of animals (p = 0.97) while UCMS group showed a significantly lower latency compared to control rats during the retention test (p < 0.001), which indicated impaired retention of emotional memory in this task. However, UCMS+infliximab group was not different from the performance of control group (p = 0.17). In the MWM test, the escape latency significantly increased in acquisition sessions and the time spent in escape platforms’s quadrant in the probe trial significantly decreased in UCMS group compared to control group (p < 0.001); infliximab reversed these effects (p < 0.001). Hippocampal BDNF levels in UCMS decreased significantly compared to the control group (p < 0.05), infliximab returned these levels to the control. Conclusions: The results of our study confirm that infliximab rescues cognitive impairment induced by unpredictable chronic mild stress model for depression in rats. Our findings support the role of TNF-a and inflammation in cognitive impairment caused by unpredictable chronic mild stress. References [1] Karson A., Demirtas T., Bayramg¨urler D., Balci F., Utkan T., 2013 Chronic administration of infliximab (TNF-a inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol. 112(5), 335−40.
P.1.j.006 Involvement of the prelimbic cortex in the disruptive effect of cannabidiol on fear memory reconsolidation C.A. Stern1 ° , L. Gazarini1 , A.C. Vanvossen1 , A.W. Zuardi2 , F.S. Guimar˜aes3 , R.N. Takahashi1 , L.J. Bertoglio1 1 Universidade Federal de Santa Catarina, Pharmacology, Florian´opolis, Brazil; 2 Universidade de S˜ao Paulo, Neuroscience and Behaviour, Ribeir˜ao Preto, Brazil; 3 Universidade de S˜ao Paulo, Pharmacology, Ribeir˜ao Preto, Brazil Purpose of the study: A dysfunctional aversive memory processing contributes to the development of the posttraumatic stress disorder [1]. The maintenance and/or strength of this memory can be attenuated by targeting pharmacologically its reconsolidation, which is regulated by brain regions such as the prelimbic (PL) cortex [2]. The major non-psychotomimetic component of the Cannabis sativa plant, cannabidiol, (CBD) is able to disrupt fear memory reconsolidation in laboratory animals through cannabinoid type-1 (CB1) receptor-mediated signaling [3]. The objective of the present study was to investigate whether CB1 receptors in the PL cortex are involved in CBD-induced reconsolidation disruption. Methods: Male Wistar rats were contextually-fear conditioned in Context A. On the next day, the retrieval session was conducted in order to induce memory labilization. It consisted of a short exposure of the animals to the same context. All treatments were performed immediately after the retrieval session. In experiment 1, the subjects received systemic injections of vehicle (VEH) or CBD
(10 mg/kg). After 1 hour, they were submitted to transcardiac perfusion for posterior evaluation of Zif268/Egr-1 protein expression along the medial prefrontal cortex (PL, cingulate and infralimbic), by immunohistochemistry. Results were expressed as the number of Zif268/Egr-1 positive cells/0.1 mm2 . In experiment 2, rats bilaterally implanted with guide cannulas received an infusion of VEH or the CB1 receptor antagonist AM251 (50 pmol/0.2 mL) into PL and, immediately after, received systemic injections of VEH or CBD (10 mg/kg). In experiment 3, rats received VEH or URB597 (30 pmol/0.2 mL), an inhibitor of the enzyme that metabolizes anandamide, into the PL. To assess reconsolidation impairment, the animals were re-exposed to Context A one day later (Test A). Freezing behavior was assessed during retrieval session and Test A as an index of fear memory. Results: VEH-treated rats displayed significantly more Zif268/Egr-1 expression in PL (40.6±1.8) and cingulate (34.5±1.5) than in infralimbic (12.4±3.7) cortex following contextual fear memory retrieval. Systemic CBD administration prevented such differences (PL: 22.1±3.7; cingulate: 23.3±4.4; infralimbic: 16.1±2.3). In experiment 2, despite all groups having presented similar freezing levels during retrieval (VEH/VEH: 77.9±3.8%; VEH/CBD: 77.8±8.4%; AM251/VEH: 73.6±9.4%; AM251/CBD: 76.3±7%), CBD-treated animals showed less freezing behavior during Test A (VEH/VEH: 75.2±8.8%; VEH/CBD: 43±8%). CB1 antagonism in the PL, however, prevented the CBD effect (AM251/VEH: 74.3±8%; AM251/CBD: 70.0±8%). In experiment 3, all groups presented similar freezing levels during the retrieval session (VEH: 78.9±2.5%; URB597: 78±4.7%). During Test A, URB597-treated group presented less freezing than the control group (VEH: 77.0±5.8%; URB597: 54.2±7.9%). Conclusions: The present work gives further support for the involvement of the PL in fear memory reconsolidation. It also indicates that the PL is a potential site for CBD disruptive effects on this process. In addition, the results suggest the indirect potentiation of the endocannabinoid system in this area is a possible mechanism to impair fear memory reconsolidation. References [1] Parsons RG, Ressler KJ. 2013. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci. 16:146−53. [2] Stern CA, Gazarini L, Vanvossen AC, Hames MS, Bertoglio LJ. 2014. Activity in prelimbic cortex subserves fear memory reconsolidation over time. Learn Mem. 21:14−20. [3] Stern CA, Gazarini L, Takahashi RN, Guimar˜aes FS, Bertoglio LJ. 2012. On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology. 37:2132−42.
P.1.j.007 Short- and long-term alteration in cognitive functioning of patients with schizophrenia I. Adamia1 ° , M. Roinishvili2 1 Tbilisi Mental Health Centre, Inpatient Department, Tbilisi, Georgia; 2 Agricultural University of Georgia, Institute of Cognitive Neurosciences, Tbilisi, Georgia Background: Many studies have stressed the importance of neurocognitive deficits in schizophrenia that represent a core feature of the pathology. Cognitive dysfunctions are present in 80% of schizophrenic patients, including deficits in attention, memory, speed processing and executive functioning, with wellknown functional consequences on daily life, social functioning and rehabilitation outcome. Recent studies have stressed that cognitive deficits, rather than the positive or negative symptoms
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p = 0.047 and z = −2.299 p = 0.021 for the mid-anterior and anterior CC portions, as well as the total CC, respectively), and a significant difference between groups in the RT of the associative pictorial task (z=2.051, p = 0.040). The current study demonstrated an association between both PTSD symptomatology and memory performance and whitematter integrity. We suggest that altered inter-hemispheric whitematter connectivity is a pathophysiological mechanism contributing to PTSD symptoms and memory deficits observed in this population. References [1] Daniels, J.K., Lamke, J.P., Gaebler, M., Walter, H., & Scheel, M. (2013). White matter integrity and its relationship to ptsd and childhood trauma--a systematic review and meta-analysis. Depress Anxiety, 30(3), 207–216. [2] Saar-Ashkenazy, R., Cohen, J., C., G., J., G., I., S., A., F., & H., S. (2014). Reduced Corpus-Callosum Volume in Posttraumatic Stress Disorder Highlights the Importance of Interhemispheric Connectivity for Associative Memory. The Journal of Traumatic Stress, 27(1), 18−26. [3] Weathers, F.W., Keane, T.M., & Davidson, J.R. (2001). Clinicianadministered PTSD scale: a review of the first ten years of research. Depress Anxiety, 13(3), 132–156.
P.1.j.005 Infliximab rescues cognitive impairment induced by unpredictable chronic mild stress in a rat model of depression T. Demirtas1 ° , T. Utkan1 , Y. Yazir2 , A. Karson3 , F. Balci4 , D. Bayramgurler5 1 Kocaeli University Medical School, Pharmacology, Izmit-Kocaeli, Turkey; 2 Kocaeli University Medical School, Histology and Embriyology, Izmit-Kocaeli, Turkey; 3 Kocaeli University Medical School, Physiology, IzmitKocaeli, Turkey; 4 Ko¸c University, Psychology, Istanbul, Turkey; 5 Kocaeli University Medical School, Dermatology, Izmit-Kocaeli, Turkey Purpose: Many depressed patients showed increased levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-a) in the clinic. Furthermore, anti-depressant compounds have anti-inflammatory effects in both depressed patients and animal models of depression. Unpredictable chronic mild stress (UCMS) is a valuable animal model of depression. We have recently reported that infliximab (a TNF-a inhibitor) decreased anhedonia and despair-like behavior in the rat chronic mild stress model of depression [1]. Increasing number of evidence also points at a relation between inflammation and cognitive impairments. The aim of this study was to investigate the effect of infliximab on UCMS-induced cognitive impairments in rats. Methods: Animals were divided into three groups (n = 12 per group): Control, UCMS and UCMS+infliximab. Control and UCMS groups received physiological saline, UCMS+infliximab group received infliximab during 8 weeks of UCMS. Infliximab was injected intraperitoneally once a week at a dose of 5 mg/kg. Briefly, UCMS and UCMS+infliximab groups were subjected to different types of stressors: Restraint for 4 h, cage tilting for 24 h, wet bedding for 24 h, swimming in 4ºC cold water for 5 min, swimming in 45ºC hot water for 5 min, pairing with another stressed animal for 48 h, level shaking for 10 min, and inversion of the light/dark cycle for 24 h. The stressors were randomly applied for 56 days and each stressor was applied 4−5 times during this time period. To determine the effects of UCMS and infliximab
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treatment on cognitive functions; locomotor activity (LA), passive avoidance (PA) and Morris water maze (MWM) tests were used. Hippocampal brain-derived neurotrophic factor (BDNF) levels of rats were evaluated immunohistochemically. Experimental results were analyzed with one-way and two-way ANOVA, post hoc Bonferroni test and Kruskal–Wallis test. Results: There were no significant differences between three groups in terms of LA (p = 0.28). In the PA test, therewas no significant difference between the first day latency of animals (p = 0.97) while UCMS group showed a significantly lower latency compared to control rats during the retention test (p < 0.001), which indicated impaired retention of emotional memory in this task. However, UCMS+infliximab group was not different from the performance of control group (p = 0.17). In the MWM test, the escape latency significantly increased in acquisition sessions and the time spent in escape platforms’s quadrant in the probe trial significantly decreased in UCMS group compared to control group (p < 0.001); infliximab reversed these effects (p < 0.001). Hippocampal BDNF levels in UCMS decreased significantly compared to the control group (p < 0.05), infliximab returned these levels to the control. Conclusions: The results of our study confirm that infliximab rescues cognitive impairment induced by unpredictable chronic mild stress model for depression in rats. Our findings support the role of TNF-a and inflammation in cognitive impairment caused by unpredictable chronic mild stress. References [1] Karson A., Demirtas T., Bayramg¨urler D., Balci F., Utkan T., 2013 Chronic administration of infliximab (TNF-a inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol. 112(5), 335−40.
P.1.j.006 Involvement of the prelimbic cortex in the disruptive effect of cannabidiol on fear memory reconsolidation C.A. Stern1 ° , L. Gazarini1 , A.C. Vanvossen1 , A.W. Zuardi2 , F.S. Guimar˜aes3 , R.N. Takahashi1 , L.J. Bertoglio1 1 Universidade Federal de Santa Catarina, Pharmacology, Florian´opolis, Brazil; 2 Universidade de S˜ao Paulo, Neuroscience and Behaviour, Ribeir˜ao Preto, Brazil; 3 Universidade de S˜ao Paulo, Pharmacology, Ribeir˜ao Preto, Brazil Purpose of the study: A dysfunctional aversive memory processing contributes to the development of the posttraumatic stress disorder [1]. The maintenance and/or strength of this memory can be attenuated by targeting pharmacologically its reconsolidation, which is regulated by brain regions such as the prelimbic (PL) cortex [2]. The major non-psychotomimetic component of the Cannabis sativa plant, cannabidiol, (CBD) is able to disrupt fear memory reconsolidation in laboratory animals through cannabinoid type-1 (CB1) receptor-mediated signaling [3]. The objective of the present study was to investigate whether CB1 receptors in the PL cortex are involved in CBD-induced reconsolidation disruption. Methods: Male Wistar rats were contextually-fear conditioned in Context A. On the next day, the retrieval session was conducted in order to induce memory labilization. It consisted of a short exposure of the animals to the same context. All treatments were performed immediately after the retrieval session. In experiment 1, the subjects received systemic injections of vehicle (VEH) or CBD
(10 mg/kg). After 1 hour, they were submitted to transcardiac perfusion for posterior evaluation of Zif268/Egr-1 protein expression along the medial prefrontal cortex (PL, cingulate and infralimbic), by immunohistochemistry. Results were expressed as the number of Zif268/Egr-1 positive cells/0.1 mm2 . In experiment 2, rats bilaterally implanted with guide cannulas received an infusion of VEH or the CB1 receptor antagonist AM251 (50 pmol/0.2 mL) into PL and, immediately after, received systemic injections of VEH or CBD (10 mg/kg). In experiment 3, rats received VEH or URB597 (30 pmol/0.2 mL), an inhibitor of the enzyme that metabolizes anandamide, into the PL. To assess reconsolidation impairment, the animals were re-exposed to Context A one day later (Test A). Freezing behavior was assessed during retrieval session and Test A as an index of fear memory. Results: VEH-treated rats displayed significantly more Zif268/Egr-1 expression in PL (40.6±1.8) and cingulate (34.5±1.5) than in infralimbic (12.4±3.7) cortex following contextual fear memory retrieval. Systemic CBD administration prevented such differences (PL: 22.1±3.7; cingulate: 23.3±4.4; infralimbic: 16.1±2.3). In experiment 2, despite all groups having presented similar freezing levels during retrieval (VEH/VEH: 77.9±3.8%; VEH/CBD: 77.8±8.4%; AM251/VEH: 73.6±9.4%; AM251/CBD: 76.3±7%), CBD-treated animals showed less freezing behavior during Test A (VEH/VEH: 75.2±8.8%; VEH/CBD: 43±8%). CB1 antagonism in the PL, however, prevented the CBD effect (AM251/VEH: 74.3±8%; AM251/CBD: 70.0±8%). In experiment 3, all groups presented similar freezing levels during the retrieval session (VEH: 78.9±2.5%; URB597: 78±4.7%). During Test A, URB597-treated group presented less freezing than the control group (VEH: 77.0±5.8%; URB597: 54.2±7.9%). Conclusions: The present work gives further support for the involvement of the PL in fear memory reconsolidation. It also indicates that the PL is a potential site for CBD disruptive effects on this process. In addition, the results suggest the indirect potentiation of the endocannabinoid system in this area is a possible mechanism to impair fear memory reconsolidation. References [1] Parsons RG, Ressler KJ. 2013. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci. 16:146−53. [2] Stern CA, Gazarini L, Vanvossen AC, Hames MS, Bertoglio LJ. 2014. Activity in prelimbic cortex subserves fear memory reconsolidation over time. Learn Mem. 21:14−20. [3] Stern CA, Gazarini L, Takahashi RN, Guimar˜aes FS, Bertoglio LJ. 2012. On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology. 37:2132−42.
P.1.j.007 Short- and long-term alteration in cognitive functioning of patients with schizophrenia I. Adamia1 ° , M. Roinishvili2 1 Tbilisi Mental Health Centre, Inpatient Department, Tbilisi, Georgia; 2 Agricultural University of Georgia, Institute of Cognitive Neurosciences, Tbilisi, Georgia Background: Many studies have stressed the importance of neurocognitive deficits in schizophrenia that represent a core feature of the pathology. Cognitive dysfunctions are present in 80% of schizophrenic patients, including deficits in attention, memory, speed processing and executive functioning, with wellknown functional consequences on daily life, social functioning and rehabilitation outcome. Recent studies have stressed that cognitive deficits, rather than the positive or negative symptoms