Behavioural Brain Research最新文献

In this study, we reassessed the suitability of one the most commonly used pharmacological animal models of Alzheimer's disease (AD) - scopolamine-induced memory impairment. The goal of the study was to explore if this animal model induces other behavioral changes associated with AD. One of the key behavioral features of AD, manifesting already during the early stages of the illness, is apathy-like behavior. We also evaluated how behavioral alterations induced by scopolamine compare to those seen in healthy aging animals. To achieve these goals, locomotor activity and short-term memory of young male Wistar rats were tested in the open field, novel object recognition (NOR) and T-maze spontaneous alternation tests before, during and after 21 daily administrations of scopolamine. Three-, ten- and nineteen-month-old male and female rats were used to measure age-related changes in these behaviors. Our data showed that although both scopolamine treatment and aging reduced the number of approaches to the objects and their exploration time during the NOR test, correlation with impaired object recognition memory was only observed in the scopolamine treated animals. Furthermore, treatment with scopolamine significantly increased the locomotor activity, which could be observed even one week after treatment discontinuation. Contrary, locomotor activity in older rats was significantly lower than that of younger rats. These findings demonstrate that the animal model of scopolamine-induced memory impairment fails to incorporate apathy-like symptoms characteristic to the AD and age-related reduction in physical activity of older rats.

Treatment-resistance in patients with schizophrenia is a major obstacle for improving outcome in patients, especially in those not gaining from clozapine. Novel research implies that glutamatergic and GABAergic abnormalities may be present in treatment-resistant patients, and preclinical research suggests that clozapine affects the GABAergic system. Moreover, clozapine may have a neuroprotective role. To investigate these issues, we conducted a systematic review to evaluate the relationship between clozapine and in vivo measures of gamma-aminobutyric acid (GABA), glutamate (glu), and N-acetylaspartate (NAA) brain levels in treatment- and ultra-treatment-resistant schizophrenia patients (TRS and UTRS). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we included three longitudinal and six cross sectional studies utilizing proton magnetic resonance spectroscopy (H-MRS) that explored brain metabolite levels in clozapine-treated patients. Findings were limited by a small number of studies and definite conclusions cannot be drawn, but the present studies may imply that clozapine reduces glutamate levels in striatal but not cortical areas, whereas glutamatergic metabolites and GABA levels may be increased in ACC in the combined group of TRS and UTRS. Clozapine may also increase NAA in cortical areas. Importantly, this review highlights the need for further clinical studies investigating the effect of clozapine on brain levels of glutamate, GABA, and NAA as well as metabolite group differences in patients with UTRS compared with TRS.

Iron is a trace metal that takes part in the maintenance of body homeostasis by, for instance, aiding in energy production and immunity. A body of evidence now demonstrates that dysfunction in iron metabolism can have detrimental effects and is intricately associated with the development of neuropsychiatric disorders, including Major Depressive Disorder (MDD), anxiety, and schizophrenia. For instance, changes in serum and central nervous system (CNS) levels of iron and in proteins mediating iron metabolism have been documented in patients grappling with the aforementioned diseases. By contrast, targeting iron metabolism by using iron chelators, for instance, has proven to be effective in alleviating disease burden. Therefore, here we review the state-of-the-art regarding the role of iron metabolism and its dysfunction in the context of neuropsychiatric disorders. Furthermore, we discuss how targeting iron metabolism can be an effective therapeutic option to tackle this class of diseases. Finally, we discuss the mechanisms linking this dysfunction to behavioral changes in these disorders. Harnessing the knowledge of iron metabolism is not only key to the characterization of novel molecular targets and disease biomarkers but also crucial to drug repurposing and drug design.

Background: Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood.

Aims: This study aimed to explore aerobic exercise-induced metabolic alterations in the brain.

Methods: We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c).

Results: Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34 %), 85 (29.11 %), and 78 (26.71 %) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus.

Conclusions: This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

"Dendritic spine pathology" refers to alterations in density and morphology of dendritic spines, crucial in corticolimbic neurons in schizophrenia. These structural neuroplasticity changes contribute to the disease's neurobiological underpinnings, alongside alterations in other brain regions, such as temporal lobe cortices like the auditory cortex (Au1) and the entorhinal cortex (Ent), involved in sensory processing, memory, and learning. The neonatal ventral hippocampus lesion (NVHL) in rats exhibits behavioral abnormalities akin to schizophrenia symptoms and corticolimbic dendritic spine pathology, mitigated by atypical antipsychotic drugs (AADs) like risperidone (RISP) and olanzapine (OLZ). This study investigated NVHL-induced dendritic spine pathology in Au1 and Ent, evaluating RISP and OLZ effects. NVHL induced dendritic spine pathology mainly by reducing the dendritic spine density in Au1 and Ent neurons; both RISP and OLZ mitigated it, increasing dendritic spine density and mushroom spine population, the ones related with synaptic strengthening, while decreasing stubby spine population. These findings underscore the role of impaired neuroplasticity in the temporal lobe cortices in schizophrenia pathophysiology and highlight the relevance of the NVHL model for studying neuroplasticity mechanisms in the disease. They also contribute to the growing understanding of targeting structural and functional neuroplasticity for novel drugs in the pharmacotherapy of the disease.

The present study aimed to investigate the potential role of estrogen in modulating the pathogenesis of dementia-type-AD phenotype, possibly by tyrosine kinase. Female Wistar rats were ovariectomized (OVX) and were treated with Diethylstilbesterol (DES), an estrogen analogue (20μg/kg/day, i.m.), and Imatinib, a tyrosine kinase inhibitor (30mg/kg/day, orally), for two months. Animals underwent surgical ovariectomy exhibited significant memory deficits in spatial memory assessment as mean dwell time, short-term memory as spontaneous alteration, and novel object recognition after a chronic period of 4 weeks. OVX animals administered with DES produced significant restoration of memory dysfunction in comparison to OVX, as exhibited by Morris water maze (p=0.0003), Y maze (p<0.0001), and NORT. Imatinib prior to DES treatment in OVX animals showed significant decline in memory functions, which confirms the potential involvement of tyrosine receptor kinase activity in improved memory functions offered by estrogen. Levels of estradiol were significantly (p<0.0001) lower in the OVX group compared to normal which was significantly (p<0.0001) restored in the OVX+E group. Biochemical estimations of TBARS, glutathione, and acetylcholinesterase levels in the brain showed a significant increase in oxidative stress among the OVX group. However, a significant restoration of oxidative changes with TBARS (p=0.0496), glutathione (p<0.0001), and acetylcholinesterase activity (p=0.0201) of OVX animals receiving DES was observed in comparison to animals receiving imatinib followed by DES. These implications in the brain signify that estrogen and tyrosine kinase play an important role in the pathogenesis of dementia. In conclusion, estrogen offers neurochemical mediation for cognition and memory possibly via modulation of tyrosine kinase signaling in female subjects.

Chronic kidney disease (CKD) and, in particular, chronic haemodialysis (HD) patients have a high risk of developing sleep disorders and executive dysfunction. Sleep disorders have a prevalence of 75 % in the haemodialysed population and several causes are behind their occurrence: sympatho-vagal imbalances, low melatonin production, vitamin D deficiency, altered cerebral haemodynamics and haemodialysis-induced vascular stress. Executive dysfunction affects about 55 % of haemodialysis patients. The causes can be ascribed to dysfunctions of the frontal lobes. HD patients show frontal brain atrophy and reduced brain activity and connectivity of several frontal and prefrontal areas. Sleep quality also has a significant impact on executive functions; inefficient and fragmented sleep reduces the efficiency of executive functions and increases the risk of dementia. Sleep deprivation also alters the connectivity and structure of several frontal areas. Thus, sleep and executive functions seem to be closely linked. Multidisciplinary care of patients with CKD and in HD appears essential to structure preventive interventions, pharmacological and non-pharmacological treatments that can improve sleep quality, preserve the integrity of executive functions and improve their quality of life.

Background and aims: Neuroinflammation, a low-grade chronic inflammation of the central nervous system, is linked to age-related neuropsychiatric disorders such as senile depression and Alzheimer's disease. Recent studies have explored controlling neuroinflammation as a novel treatment strategy. Molecular hydrogen shows anti-inflammatory effects. However, its impacts on neuroinflammation and age-related neuropsychiatric disorders remain unelucidated. We investigated molecular hydrogen's effects on microglial activation, neuroinflammation, depressive-like behavior, and short-term cognitive decline in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Methods: Six-week-old SAMP8 or senescence-accelerated mouse-resistant 1 (SAMR1) mice received hydrogen-rich jelly (HRJ) or placebo jelly (PJ) from six weeks of age for 26-28 weeks. Depressive-like behavior was assessed using tail suspension and forced swimming tests, while cognitive function was evaluated using the Y-maze and object recognition tests. Brain tissues were used for immunohistochemical studies or to measure pro-inflammatory cytokine levels via enzyme-linked immunosorbent assay (ELISA).

Results: HRJ intake reduced immobility time in both tail suspension and forced swimming tests and enhanced visual cognitive and spatial working memory in SAMP8 mice. Additionally, HRJ intake suppressed the 8-hydroxy-2'-deoxyguanosine (8-OHdG), Iba1, and cleaved caspase 3 expression levels in the medial prefrontal cortex and hippocampal dentate gyrus. Furthermore, HRJ intake significantly lowered IL-6 levels in brain tissues of SAMP8 mice.

Conclusions: These findings suggest that molecular hydrogen treatment may regulate neuroinflammation induced by activated microglia and improve depressive-like behavior and short-term cognitive impairment in SAMP8 mice.

Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one. Therefore, this work explored the effects of acute AMPA and glyphosate on spatial learning, memory and navigation in female rats. Sprague Dawley rats received a single injection (i.p.) of: (i) vehicle; (ii) 10 or 100 mg/kg of AMPA; or (iii) 10 or 100 mg/kg of glyphosate; subsequently, the Barnes maze paradigm was performance. Animals from the control group decreased latency and the attempts to solve the Barnes maze; and increased the degree of orientation when compared first training sessions (S1) vs. the last one (S4; p < 0.05). In contrast, both 10 and 100 mg/kg of glyphosate and 100 mg/kg of AMPA prevented the decrease in latency and attempts; and the increase of orientation (p > 0.05; S1 vs. S4). Both treatments decreased the use of the spatial navigation strategy (p < 0.05). Besides, glyphosate at the higher dose but not AMPA impaired the spatial memory during the test. Our findings suggest that acute exposure to glyphosate and AMPA similarly affected spatial orientation, navigations, learning and/or memory.

Adult rats communicate using ultrasonic vocalization (USV) frequencies indicating negative (22 kHz) or positive (50 kHz) affective states. Playback of USVs can serve as an ethologically translational method to study affective processing in response to socially communicated states. However, few studies have examined behavioral and neural effects of USV playback in both male and female rats. Here, adult male and female Sprague-Dawley rats experienced a 20-min open field test (OFT) with either silence, 22 kHz, or 50 kHz recorded USV playback. Center exploration and locomotor activity were analyzed to characterize sex differences in playback effects. Results suggest that females display greater sensitivity to frequency-specific effects of USV playback in this paradigm compared to males. 50 kHz USV playback evoked an immediate increase in center exploration and locomotor activity in females, indicating the appetitive nature of 50 kHz USVs. Initially, 22 kHz playback inhibited center exploration in the OFT compared to 50 kHz. However, females exhibited a switch in behavioral strategy in response to 22 kHz following prolonged playback. Following OFT, neural activity was quantified via the immediate early gene cFos. Results from cFos quantification showed sex- and region-specific differences in neural recruitment in areas of the brain associated with affective processing, including the prefrontal cortex, amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. Taken together, this work provides a normative baseline for understanding how sex influences behavioral and neural responses to USV playback, which can be leveraged to study anxiety, communication, and affect in an ethologically relevant assay.