Baseline prepulse inhibition dependency of orexin A and REM sleep deprivation.

RATIONALE: Prepulse inhibition (PPI) impairment reflects sensorimotor gating problems, i.e. in schizophrenia. This study aims to enlighten the role of orexinergic regulation on PPI in a psychosis-like model. OBJECTIVES: In order to understand the impact of orexinergic innervation on PPI and how it is modulated by age and baseline PPI (bPPI), chronic orexin A (OXA) injections was carried on non-sleep-deprived and sleep-deprived rats that are grouped by their bPPI. METHODS: bPPI measurements were carried on male Wistar rats on P45 or P90 followed by grouping into low-PPI and high-PPI rats. The rats were injected with OXA twice per day for four consecutive days starting on P49 or P94, while the control groups received saline injections. 72 h REMSD was carried on via modified multiple platform technique on P94 and either OXA or saline was injected during REMSD. PPI tests were carried out 30 min. after the last injection. RESULTS: Our previous study with acute OXA injection after REMSD without bPPI grouping revealed that low OXA doses might improve REMSD-induced PPI impairment. Our current results present three important conclusions: (1) The effect of OXA on PPI is bPPI-dependent and age-dependent. (2) The effect of REMSD is bPPI-dependent. (3) The effect of OXA on PPI after REMSD also depends on bPPI. CONCLUSION: Orexinergic regulation of PPI response with and without REMSD can be predicted by bPPI levels. Our findings provide potential insights into the regulation of sensorimotor gating by sleep/wakefulness systems and present potential therapeutic targets for the disorders, where PPI is disturbed.

Enhancing CAR-T cells: unleashing lasting impact potential with phytohemagglutinin activation in in vivo leukemia model.

Chimeric antigen receptor T (CAR-T) cell therapy holds great promise as an innovative immunotherapeutic approach for cancer treatment. To optimize the production and application of CAR-T cells, we evaluated the in vivo stability and efficacy capacities of CAR-T cells developed under different conditions. In this study, CAR-T cells were activated using Phytohemagglutinin (PHA) or anti-CD3&anti-CD28 and were compared in an in vivo CD19+B-cell cancer model in mouse groups. Our results demonstrated that CAR-T cells activated with PHA exhibited higher stability and anti-cancer efficacy compared to those activated with anti-CD3&anti-CD28. Specifically, CAR19BB-T cells activated with PHA exhibited continuous proliferation and long-term persistence without compromising their anti-cancer efficacy. Kaplan-Meier survival analysis revealed prolonged overall survival in the CAR-T cell-treated groups compared to the only tumor group. Furthermore, specific LTR-targeted RT-PCR analysis confirmed the presence of CAR-T cells in the treated groups, with significantly higher levels observed in the CAR19BB-T (PHA) group compared to other groups. Histopathological analysis of spleen, kidney, and liver tissue sections indicated reduced inflammation and improved tissue integrity in the CAR-T cell-treated groups. Our findings highlight the potential benefits of using PHA as a co-stimulatory method for CAR-T cell production, offering a promising strategy to enhance their stability and persistence. These results provide valuable insights for the development of more effective and enduring immunotherapeutic approaches for cancer treatment. CAR-T cells activated with PHA may offer a compelling therapeutic option for advancing cancer immunotherapy in clinical applications.

CONNECTOME or COLLECTOME? A NEUROPHILOSOPHICAL Perspective.

Human beings exist in a biological and social system from a micro to a macro level, by means of "collectivity", a dynamic collaboration that they have established together with the elements in that system in a way to complement each other and realize a common goal. Many neuroscientific concepts used today to explain neuronal processes from which mental functions originate are far from searching answers to traditional philosophical questions. However, the brain - as the generator of highly abstract concepts - is so complex that it cannot be explained by minimalistic approaches. The concept of connectome used in recent years to describe neuronal connections from which brain functions originate exemplifies this minimalistic approach, because it only describes structural and functional connections but does not look at brain functions in a holistic view. For this reason, we propose the concept of collectome - to replace the concept of connectome - that describes a homeomorphic and homotopic neuronal framework that has a bicontinuous style of work from micro to macroscale which is based on fractal rules.

The sex-dependent anti-depressant-like effects of zeatin in rat behavioral despair model as a candidate A2A receptor ligand.

Zeatin, an adenine-derivative cytokinin has well-established functions in plants. It is also suggested to activate A2A receptors in animals, however, there is limited knowledge of its effects. The main objective of this study is to evaluate the possible effects of zeatin on depression, and our hypothesis is that zeatin might induce an anti-depressant effect via A2A receptor-linked pathways. The forced swim test was used to create a depression-like model on female and male rats. A balanced zeatin isomer mixture (80 % trans-zeatin (tZ), 20 % cis-zeatin (cZ)) was administered intraperitoneally to analyze the effects. Caffeine with a suboptimal dose (2 mg/kg) was used as a known ligand of A2A receptor. Finally, a molecular docking study was also implemented to compare caffeine and tZ in the ligand binding site of A2A receptor. We demonstrate that (1) there is a clear sex-dependent difference in the susceptibility to depression-like symptoms, where female rats in the metestrus phase display higher depressive-like behavior and lower responses to the anti-depressant-like effects of pharmacological applications; (2) 10 mg/kg zeatin exerts an anti-depressant-like effect for both females and males without affecting locomotor activity; (3) 8 mg/kg tZ alone replicates this effect for both sexes, (4) the effect of zeatin is also differential for either sex and (5) the similar effect of caffeine and zeatin implies that the effect might be exerted via A2A receptor mediated pathways. Computational analysis further yielded similar binding patterns for both ligands. In conclusion, zeatin might have a potential therapeutic use in depression, acting via adenosinergic pathways.

Dose-dependent and opposite effects of orexin A on prepulse inhibition response in sleep-deprived and non-sleep-deprived rats.

Orexin is a novel neurotransmitter released from lateral hypothalamus, that is a crucial modulator in sleep/wakefulness system. Recent studies also suggest its possible role in the neurodevelopmental disorders, such as schizophrenia. Our study consists of two experiments, where we investigate the effect of orexin A (OXA), one of two isoforms of orexin that can pass blood brain barrier, on the prepulse inhibition of acoustic startle reflex. The first experiment tested the effect of OXA on PPI response of non-sleep-deprived rats via intraperitoneal injection 30min before testing. Our results show that 40µg/kg OXA attenuates PPI% at 78dB and 86dB prepulse intensities. The second experiment utilized 72-h REM sleep deprivation, as a model for sleep-deprivation-induced impairment of PPI response. Here, we tested the effect of OXA on PPI% of sleep-deprived rats via intraperitoneal injection at the last 30min of sleep deprivation, testing for PPI immediately afterwards. Our results showed that (1) sleep deprivation attenuates the PPI% at 74dB, 78dB and 86dB prepulse intensities and (2) 10µg/kg OXA completely restores the impaired PPI% at 78dB only, where the highest PPI% impairment was observed. These results suggest that orexin A modulates PPI response in rats in a dose-dependent manner, oppositely for non-sleep-deprived and sleep-deprived rats, and a more detailed investigation for the etiology of this effect should follow.

Lesions of the paraventricular thalamic nucleus attenuates prepulse inhibition of the acoustic startle reflex.

The paraventricular thalamic nucleus (PVT) is a midline nucleus with strong connections to cortical and subcortical brain regions such as the prefrontal cortex, amygdala, nucleus accumbens and hippocampus and receives strong projections from brain stem nuclei. Prepulse inhibition (PPI) is mediated and modulated by complex cortical and subcortical networks that are yet to be fully identified in detail. Here, we suggest that the PVT may be an important brain region for the modulation of PPI. In our study, the paraventricular thalamic nuclei of rats were electrolytically lesioned. Two weeks after the surgery, the PPI responses of the animals were monitored and recorded using measurements of acoustic startle reflex. Our results show that disruption of the PVT dramatically attenuated PPI at prepulse intensities of 74, 78 and 86dB compared to that in the sham lesion group. Thus, we suggest that the PVT may be an important part of the PPI network in the rat brain.

Data on pharmacological applications and hypothermia protection against in vitro oxygen-glucose-deprivation-related neurodegeneration of adult rat CA1 region.

In this data article, the level of chemical neuroprotection against oxygen-glucose-deprivation (OGD)-related neurodegeneration in CA1 was analyzed using the measurements on CA1 stratum pyramidale (CA1sp) width. Adult rat hippocampal slices were incubated in OGD medium for 60 min to create a model for severe ischemic conditions. Alternatively, control slices were incubated in artificial cerebrospinal fluid (ACSF) for 60 min. A study of OGD induced neurodegeneration and partial prevention by pharmacological agents reported; baclofen, memantine and l-carnitine effects were included. Also, the use of hypothermia was reported (P. Öz, H. Saybasili, 2016) [1]. Here, the use CA1sp width measurements on Nissl-stained hippocampal slices is introduced as a valid and affordable method for detecting the level of neurodegeneration and neuroprotection on hippocampal slices. The protective effect of hypothermia was found to be more pronounced compared to other agents.

In vitro detection of oxygen and glucose deprivation-induced neurodegeneration and pharmacological neuroprotection based on hippocampal stratum pyramidale width.

Ischemia is one of the most prominent risk factors of neurodegenerative diseases such as Alzheimer's disease. The effects of oxygen and glucose depletion in hippocampal tissue due to ischemia can be mimicked in vitro using the oxygen and glucose deprivation (OGD) model. In this study, we applied OGD on acute rat hippocampal slices in order to design an elementary yet quantitative histological technique that compares the neuroprotective effects of (l)-carnitine to known neuroprotectors, such as the N-methyl-d-aspartate (NMDA) receptor antagonist memantine and the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen. The level of neurodegeneration and the efficiency of pharmacological applications were estimated via stratum pyramidale width measurements in CA1 and CA3 regions of Nissl-stained 200-µm thick hippocampal slices. We demonstrated that (l)-carnitine is an effective pharmacological target against the neurodegeneration induced by in vitro ischemia in a narrow range of concentrations. Even though the effect of chemical neuroprotection was significant, full recovery was not achieved in the dose interval of 5-100µM. In addition to chemical applications, hypothermia was used as a physical neuroprotection against ischemia-related neurodegeneration. Our results showed that incubation of slices for 60min at 4°C provided the same level of neuroprotection as the most effective doses of memantine, baclofen, and (l)-carnitine.

Action potential initiation in a multi-compartmental model with cooperatively gating Na channels in the axon initial segment.

Somatic action potentials (AP) of cortical pyramidal neurons have characteristically high onset-rapidness. The onset of the AP waveform is an indirect measure for the ability of a neuron to respond to temporally fast-changing stimuli. Theoretical studies on the pyramidal neuron response usually involves a canonical Hodgkin-Huxley (HH) type ion channel gating model, which assumes statistically independent gating of each individual channel. However, cooperative activity of ion channels are observed for various cell types, meaning that the activity (e.g. opening) of one channel triggers the activity (e.g. opening) of a certain fraction of its neighbors and hence, these groups of channels behave as a unit. In this study, we describe a multi-compartmental conductance-based model with cooperatively gating voltage-gated Na channels in the axon initial segment. Our model successfully reproduced the somatic sharp AP onsets of cortical pyramidal neurons. The onset latencies from the initiation site to the soma and the conduction velocities were also in agreement with the previous experimental studies.