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Abstract Background Alzheimer's disease is accompanied by an abnormal high accumulation of cis-P tau. However, the long-term changes in behavior following tau accumulation remains under debate. The present study investigated the long-term effects of tauopathy on learning and memory, synaptic plasticity, and hippocampal cell numbers. Results Cis-P tau was microinjected into the dorsal hippocampus to generate Alzheimer’s like-disease model in C57BL/6 mice. Cis-P tau injected animals showed a significant impairment in learning and memory in Y-maze and Barnes maze tests. In another group of animals, the generation of long-term potentiation (LTP) was evaluated in hippocampal slices 7 months after cis-P tau injection. LTP induction was disrupted only in the dorsal but not ventral hippocampal slices. The basal synaptic transmission was also reduced in dorsal hippocampal slices. In addition, hippocampal sampling was done, and the number of cells was assessed by Nissl staining. Obtained results indicated that the number of survived cells was significantly reduced in the dorsal and ventral hippocampus of cis P-tau injected animals compared to the animals in control group. However, the decrement of cell number was higher in the dorsal compared to the ventral hippocampus. Conclusions In conclusion, intra-hippocampal cis-P tau injection produced learning and memory impairment at 7 months after its injection. This impairment might result from LTP disruption and a significant decrease in the number of neurons in the dorsal hippocampus. Graphical Abstract

Adipose derived stem cells (ADSCs) are multipotent and can transdifferentiate into neural stem cells. We investigated the transdifferentiation of ADSCs to neural phenotype (NP) cells using selegiline and two-dimensional electrophoresis (2-DE). The perinephric and inguinal fat of rats was collected and used to isolate ADSCs that were characterized by immunophenotyping using flow cytometry. The ADSCs were differentiated into osteogenic and lipogenic cells. The NP cells were generated using 10−9 mM selegiline and characterized by immunocytochemical staining of nestin and neurofilament 68 (NF-68), and by qRT-PCR of nestin, neurod1 and NF68. Total protein of ADSCs and NP cells was extracted and their proteome patterns were examined using 2-DE. ADSCs carried CD73, CD44 and CD90 cell markers, but not CD34. ADSCs were differentiated into osteocyte and adipocyte lineages. The differentiated NP cells expressed nestin, neuro d1 and NF-68. The proteome pattern of ADSCs was compared with that of NP cells and eight spots showed more than a two fold increase in protein expression. The molecular weights and isoelectric points of these highly expressed proteins were estimated using Melanie software. We compared these results with those of the mouse proteomic database using the protein isoelectric point database, and the functions of the eight proteins in differentiation of NP cells were predicted using the UniProt database. The probable identities of the proteins that showed higher expression in NP cells included cholinesterase, GFRa2, protein kinase C (PKC-eta) and RING finger protein 121. The sequences of the proteins identified from mouse database were aligned by comparing them with similar proteins in rat database using the Basic Local Alignment Search Tool (BLAST). The E values of all aligned proteins were zero, which indicates consistency of the matched protein. These proteins participate in differentiation of the neuron and their overexpression causes ADSCs transdifferentiation into NP cells. [ABSTRACT FROM AUTHOR]

Background: Axon regeneration in adult CNS is limited by the presence of inhibitory proteins associated with myelin. Although blocking PKC activity attenuates the ability of CNS myelin to inhibit neurite outgrowth, the role as well as mechanisms underlying the remyelination inhibition in CNS are still largely unknown. Considering the role of PKC in axonal regeneration and the vulnerability of optic chiasm in multiple sclerosis (MS), we assessed the effect of PKC inhibition on remyelination of lysolecithin induced demyelinated optic chiasm. Materials and Methods: Demyelination was induced by stereotaxic intra-chiasmatic injection of 1μl lysolecithin (%1) in male mice. Intracerebroventricular daily injection of a PKC inhibitor (GO6976) was done for 14 days post-lesion. Demyelination and remyelination patterns in optic chiasm were confirmed through histological verification and electrophysiological study using Luxol fast blue staining and visual evoked potentials (VEP) recording, respectively. Results: In lysolecithin treated animals, demyelination was mostly marked at days 3 and 7 post-lesion and an incomplete remyelination occurred at day 14 post-lesion. VEP recording showed increased P-latency at the days 3 and 7 post-lesion while it partially decreased at day 14. Following the inhibition of PKC, while the extent of demyelination and P-latency slightly decreased at the days 3 and 7 post-lesion, it recovered at day 14. VEP recording data were confirmed by histological verification. Conclusion: Inhibition of PKC activity could represent a potential therapeutic approach for stimulating the remyelination process in the context of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Low frequency stimulation (LFS) has an inhibitory effect on rapid perforant path kindling acquisition. In the present study the role of adenosine A1 and A2A receptors in mediating this inhibitory effect was investigated. Rats were kindled by perforant path stimulation using rapid kindling procedures (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50–150 μA) was applied to the perforant path immediately after termination of each rapid kindling stimulation. 1,3-Dimethyl-8-cyclopenthylxanthine (CPT; 50 μM), a selective A1 antagonist and ZM241385 (ZM, 200 μM), a selective A2A antagonist were daily microinjected into the lateral ventricle 5 min before kindling stimulations. LFS had an inhibitory effect on kindling development. Pretreatment of animals with CPT reduced the inhibitory effect of LFS on kindling rate and suppressed the effects of LFS on potentiation of population EPSP during kindling acquisition. In addition, CPT was able to antagonize the effects of LFS on kindling-induced increase in early (10–50 ms intervals) and late (300–1000 ms intervals) paired pulse depression. ZM pretreatment had no effect on antiepileptogenic effects of LFS in kindling acquisition. In addition, LFS prevented the kindling-induced elevation of cyclic AMP (cAMP) levels in kindled animals. Based on these results, we suggest that the antiepileptogenic effects of LFS on perforant path kindling might be mediated through activation of adenosine A1, but not A2A receptors. Moreover, modulation of cAMP levels by LFS may potentially be an important mechanism which explains the anticonvulsant effects of LFS in kindled seizures. [Copyright &y& Elsevier]

Objective: We examined the survival, integration, differentiation and functional repair potency of human induced pluripotent stem cells- derived neural progenitors (hiPS-NPs) following transplantation into the retina of rats with crushed optic nerve. Materials and Methods: The Royan hiPs were induced to NPs using Noggin and Retinoic acid during 3 week. Q RT- PCR, Immunocytochemistry and flowcytometry were used to detect markers genes and proteins of neural progenitor cells. The expression of ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF) and Insulin-like growth factor 1(IGF1) by hiPS-NPs were detected by ElISA. One hundred rats were randomly divided into four groups: normal control, optic nerve crushed rats injected with PBS , optic nerve crushed rats injected with hiPS-NPs, or injected with dead hiPS-NPs. Cells was labeled by red fluorescent CM-DiI and injected into the vitreous cavity one day after breaking inner limiting membrane by acid aminoadipic acid. Visual evoked potential recording was done for evaluating functional recovery of optic apparatus. Transplanted cells fate was then evaluated using Immunohistofluorescence. Results: hiPS-NPs characterization showed anterior cell characteristics with high expression level of PAX6. ELISA showed neurotrophic factors secretion by hiPS-NPs. Functional analysis using VEPs showed significant amplitude recovery in animals transplanted with live cells. Sixty days after transplantation hiPS-NPs were integrated into the ganglion cell layer of retina and some of them expressed markers of ganglion cells. Retrograde labeling with DiI showed higher number of projection cells in retina. Conclusion: hiPS-NPs transplantation was able to protect retinal ganglion cells after optic nerve injury, and integrated and differentiated in to ganglion cell layer. These cells may provide new therapeutic approach for traumatic optic nerve diseases. [ABSTRACT FROM AUTHOR]

This study aims to investigate whether glial cells, in particular putative astrocytes, contribute to functional distinctions between the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus. To evaluate this, we performed three different behavioral tasks (i.e., Morris water maze; MWM, Passive avoidance; PA, T-maze place preference; TPP) to determine whether the DH, IH, and VH are necessary for each task. Sensitivity of behavioral tasks was confirmed using lidocaine (2 %, 1 μl) reversible inactivation. Subsequently, we examined the effects of silencing astrocytes, using fluorocitrate (FC, 1 mM/1 μl), into the DH, IH, and VH on these tasks. The effects of drugs were examined separately. We observed that injection of FC into the DH resulted in a significant impairment in MWM performance. In contrast, while FC injections into the IH or VH did not prevent platform localization during the acquisition phase, rats showed difficulty recalling the target zone during the retrieval phase. In the PA test, FC injection into the VH impaired task learning and memory. During the acquisition phase, FC injection into the DH or IH did not differ from the control in the number of shocks; however, during retrieval, there was a significant decrease in the latency before entering the dark chamber. The TPP test performance was impaired by FC injection in the IH. In sum, we show that glial cells, especially astrocytes in specific functional regions of the hippocampus, play distinct roles in processing aversive and rewarding experiences and contribute to the functional organization of the hippocampal longitudinal axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) has demonstrated potential in mitigating Alzheimer's disease (AD). However, the invasive nature of DBS presents challenges for its application. The olfactory bulb (OB), showing early AD-related changes and extensive connections with memory regions, offers an attractive entry point for intervention, potentially restoring normal activity in deteriorating memory circuits., Aims: Our study examined the impact of electrically stimulating the OB on working memory as well as pathological and electrophysiological alterations in the OB, medial prefrontal cortex, hippocampus, and entorhinal cortex in amyloid beta (Aβ) AD model rats., Methods: Male Wistar rats underwent surgery for electrode implantation in brain regions, inducing Alzheimer's-like disease. Bilateral olfactory bulb (OB) electrical stimulation was performed for 1 hour daily to the OB of stimulation group animals for 18 consecutive days, followed by the evaluations of histological, behavioral, and local field potential signal processing., Results: OB stimulation counteracted Aβ plaque accumulation and prevented AD-induced working memory impairments. Furthermore, it prompted an increase in power across diverse frequency bands and enhanced functional connectivity, particularly in the gamma band, within the investigated regions during a working memory task., Conclusion: This preclinical investigation highlights the potential of olfactory pathway-based brain stimulation to modulate the activity of deep-seated memory networks for AD treatment. Importantly, the accessibility of this pathway via the nasal cavity lays the groundwork for the development of minimally invasive approaches targeting the olfactory pathway for brain modulation., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects., Methods: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI., Results: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01)., Conclusions: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma., (© 2024. The Author(s).)

In this study, the electrophysiological and biochemical consequences of repeated exposure to morphine in male rats on glutamatergic synaptic transmission, synaptic plasticity, the expression of GABA receptors and glutamate receptors at the temporoammonic-CA1 synapse along the longitudinal axis of the hippocampus (dorsal, intermediate, ventral, DH, IH, VH, respectively) were investigated. Slice electrophysiological methods, qRT-PCR, and western blotting techniques were used to characterize synaptic plasticity properties. We showed that repeated morphine exposure (RME) reduced excitatory synaptic transmission and ability for long-term potentiation (LTP) in the VH as well as eliminated the dorsoventral difference in paired-pulse responses. A decreased expression of NR2B subunit in the VH and an increased expression GABAA receptor of α1 and α5 subunits in the DH were observed following RME. Furthermore, RME did not affect the expression of NR2A, AMPA receptor subunits, and γ2GABAA and GABAB receptors in either segment of the hippocampus. In sum, the impact of morphine may differ depending on the region of the hippocampus studied. A distinct change in the short- and long-term synaptic plasticity along the hippocampus long axis due to repeated morphine exposure, partially mediated by a change in the expression profile of glutamatergic receptor subunits. These findings can be useful in further understanding the cellular mechanism underlying deficits in information storage and, more generally, cognitive processes resulting from chronic opioid abuse., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate the effects of intranasal air-puffing on cognitive impairments and brain cortical activity following one night of partial sleep deprivation (PSD) in adults. A total of 26 healthy adults underwent the numerical Stroop test (NST) and electroencephalography (EEG) before and after one night of PSD. Following PSD, subjects in the treatment group ( n = 13) received nasal air-puffs (5 Hz, 3 min) before beginning the NST and EEG recording. Administration of nasal air-puffs in the treatment group restored the PSD-induced increase in error rate and decrease in reaction time and missing rate in the NST. Intranasal air-puffs recovered the PSD-induced augmentation of delta and theta power and the reduction of beta and gamma power in the EEG, particularly in the frontal lobes. Intranasal air-puffing also almost reversed the PSD-induced decrease in EEG signal complexity. Furthermore, it had a restorative effect on PSD-induced alteration in intra-default mode network functional connectivity in the beta and gamma frequency bands. Rhythmic nasal air-puffing can mitigate acute PSD-induced impairments in cognitive functions. It exerts part of its ameliorating effect by restoring neuronal activity in cortical brain areas involved in cognitive processing.

Aims: In this study, the anticonvulsant action of closed-loop, low-frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated., Methods: Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test., Results: Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre-ictal, ictal, and post-ictal periods. Meanwhile, DBS increased the post-ictal-to-pre-ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post-ictal-to-pre-ictal ratio of coherence. In addition, DBS increased the hippocampal-mPFC coupling in pre-ictal period and decreased the coupling in the ictal and post-ictal periods., Conclusion: Applying closed-loop, low-frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low-frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non-seizure state in subjects that received DBS., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The impact of dopamine on synaptic plasticity and cognitive function following seizure is not well understood. Here, using optogenetics in the freely behaving animal, we examined exploratory behavior and short-term memory in control and kindled male mice during tonic stimulation of dopaminergic neurons within the ventral tegmental area (VTA). Furthermore, using field potential recording, we compared the effect of dopamine on synaptic plasticity in stratum radiatum and stratum oriens layers of both ventral and dorsal hippocampal CA1 regions, and again in both control and kindled male mice. Our results demonstrate that tonic stimulation of VTA dopaminergic neurons enhances novelty-driven exploration and short-term spatial memory in kindled mice, essentially rescuing the seizure-induced cognitive impairment. In addition, we found that dopamine has a dual effect on LTP in control versus kindled mice, such that application of dopamine prevented LTP induction in slices from control mice, but rescued LTP in slices taken from the kindled animal. Taken together, our results highlight the potential for dopaminergic modulation in improving synaptic plasticity and cognitive function following seizure., (Copyright © 2024 the authors.)

Epilepsy is a neurological disorder that remains difficult to treat due to the lack of a clear molecular mechanism and incomplete understanding of involved proteins. To identify potential therapeutic targets, it is important to gain insight into changes in protein expression patterns related to epileptogenesis. One promising approach is to analyze proteomic data, which can provide valuable information about these changes. In this study, to evaluate the changes in gene expression during epileptogenesis, LC-MC 2 analysis was carried out on hippocampus during stages of electrical kindling in rat models. Subsequently, progressive changes in the expression of proteins were detected as a result of epileptogenesis development. In line with behavioral kindled seizure stages and according to the proteomics data, we described epileptogenesis phases by comparing Stage3 versus Control (S3/C0), Stage5 versus Stage3 (S5/S3), and Stage5 versus Control group (S5/C0). Gene ontology analysis on differentially expressed proteins (DEPs) showed significant changes of proteins involved in immune responses like Csf1R, Aif1 and Stat1 during S3/C0, regulation of synaptic plasticity like Bdnf, Rac1, CaMK, Cdc42 and P38 during S5/S3, and nervous system development throughout S5/C0 like Bdnd, Kcc2 and Slc1a3.There were also proteins like Cox2, which were altered commonly among all three phases. The pathway enrichment analysis of DEPs was also done to discover molecular connections between phases and we have found that the targets like Csf1R, Bdnf and Cox2 were analyzed throughout all three phases were highly involved in the PPI network analysis as hub nodes. Additionally, these same targets underwent changes which were confirmed through Western blotting. Our results have identified proteomic patterns that could shed light on the molecular mechanisms underlying epileptogenesis which may allow for novel targeted therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Normal aging in mammals is accompanied by a decline in learning and memory. Dopamine plays a vital role in regulating cognitive functions, but it declines with age: During non-pathological aging, dopamine levels, receptors, and transporters decrease. Regarding the role of the dopaminergic system's changes in old age, we examined the effect of age and applied dopamine on working memory, synaptic transmission, and long-term potentiation (LTP) induction and maintenance in young adult and mature adult mice. We employed the Y-maze spontaneous alteration test to evaluate working memory. Maturation had no observed effect on working memory performance. Interestingly, working memory performance increased following intracerebroventricular administration of dopamine only in mature adult mice. We employed evoked field potential recording (in vitro) to assess the effects of age and maturation on the long-term potentiation (LTP) induction and maintenance. There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. However, the application of dopamine on mature adult murine slices increased LTP magnitude compared to slices from young adults. According to the obtained results, it may be concluded that hippocampal neural excitability increased in mature adult subjects, and application of dopamine abolished the difference in neural excitability among young mature and adult mature groups; which was accompanied with increment of working memory and synaptic potentiation in mature adult animals., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

There is growing evidence that the hippocampus comprises diverse neural circuits that exhibit longitudinal variation in their properties, however, the intermediate region of the hippocampus has received comparatively little attention. Therefore, this study was designed to compared short- and long-term synaptic plasticity between the dorsal and intermediate regions of the hippocampus in normal and PTZ-kindled rats. Short-term plasticity was assessed by measuring the ratio of field excitatory postsynaptic potentials' (fEPSPs) slope in response to paired-pulse stimulation at three different inter-pulse intervals (20, 80, and 160 ms), while long-term plasticity was assessed using primed burst stimulation (PBS). The results showed that the basal synaptic strength differed between the dorsal and intermediate regions of the hippocampus in both control and kindled rats. In the control group, paired-pulse stimulation of Schaffer collaterals resulted in a significantly lower fEPSP slope in the intermediate part of the hippocampus compared to the dorsal region. Additionally, the magnitude of long-term potentiation (LTP) was significantly lower in the intermediate part of the hippocampus compared to the dorsal region. In PTZ-kindled rats, both short-term facilitation and long-term potentiation were impaired in both regions of the hippocampus. Interestingly, there was no significant difference in synaptic plasticity between the dorsal and intermediate regions in PTZ-kindled rats, despite impairments in both regions. This suggests that seizures eliminate the regional difference between the dorsal and intermediate parts of the hippocampus, resulting in similar electrophysiological activity in both regions in kindled animals. Future studies should consider this when investigating the responses of the dorsal and intermediate regions of the hippocampus following PTZ kindling., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Depression is a debilitating condition that affects the mind and the individual's body. The improving effects of saffron on depression and anxiety have long been discussed, with limited information about the molecular mechanism of action., Hypothesis/purpose: Investigating the effect of saffron carotenoids, Crocin and Crocetin, on depression and anxiety in rats by emphasizing some signaling pathways involved., Study Design: Depression and anxiety were induced in rats via unpredictable chronic mild stress (UCMS). Then different rat groups were treated with Crocin, Crocetin, Fluoxetine, and vehicle. Behavioral tests were done before and after treatment., Methods: The serum Serotonin and Corticosterone and the expression of some hippocampal signaling proteins were studied. Furthermore, bioinformatics tools were used to predict the interactions of Crocin/ Crocetin with the Serotonin transporter and NMDA receptor subunit NR2B. Then, the patch-clamp was used to study the interaction of Crocetin with the NMDA receptor., Results: Various behavioral tests confirmed the induction of depression and the improvement of depression by these natural carotenoids. In addition, Crocin/ Crocetin significantly increased the decreased serum Serotonin and reduced the increased serum Corticosterone in the depressed groups. They also increased or caused a trend of increase in the CREB, ERK, BAD, BDNF, p11, and 5-HT1B expression in the hippocampus of the depressed groups. In addition, there were an increase or a trend in p-CREB/CREB, p-ERK 1/2 /ERK 1/2 , and p-BAD/BAD ratios in the Crocin/ Crocetin treated depressed groups. However, the NR2B and FOXO3a expression showed a trend of decrease in depressed groups after treatment. The bioinformatics data indicated that Crocin/ Crocetin could bind to the Serotonin transporter (SLC6A4) and NR2B subunit of the NMDA receptor. Both carotenoids bind to the same site as Fluoxetine in the SLC6A4. However, they bound to different sites on the NR2B. So, Crocetin binds to NR2B at the same site as Ifenprodil. But Crocin bound to another site. The whole cell patch-clamp recording on the normal rat hippocampus revealed a significant decrease in the NMDA peak amplitude after Crocetin treatment, indicating its inhibitory effect on this receptor., Conclusion: The antidepressant activities of Crocin/ Crocetin are possibly due to their effects on Serotonin and Corticosterone serum concentrations, NR2B expression, and the downstream signaling pathways. Furthermore, these natural carotenoids, like Fluoxetine, induced an increasing tendency in p11 and 5HT1B in depressed rats., Competing Interests: Declaration of Competing Interest I hereby declare that the disclosed information is correct and that no other situation of real, potential or apparent conflict of interest is known to me and other authors. I undertake to inform you of any change in these circumstances, including if an issue arises during the course of the submission or work itself., (Copyright © 2023. Published by Elsevier GmbH.)

Drug addiction is a worldwide social and medical disorder. More than 50 percent of drug abusers start their substance abuse in adolescence between the ages of 15-19. Adolescence is a sensitive and crucial period for the development and maturity of the brain. Chronic exposure to morphine, particularly during this period, lead to long-lasting effects, including effects that extend to the next generation. The current study examined the intergenerational effects of paternal morphine exposure during adolescence on learning and memory. In this study, male Wistar rats were exposed to increasing doses of morphine (5-25 mg/kg, s.c.) or saline for 10 days at postnatal days (PND) 30-39 during adolescence. Following a 20-day drug-free period, the treated male rats were mated with naïve females. Adult male offspring (PND 60-80) were tested for working memory, novel object recognition memory, spatial memory, and passive avoidance memory using the Y-Maze, novel object recognition, Morris water maze, and shuttle box tests, respectively. The spontaneous alternation (as measured in the Y-Maze test) was significantly less in the morphine-sired group compared to the saline-sired one. The offspring showed significantly less discrimination index in the novel object recognition test when compared to the control group. Morphine-sired offspring tended to spend significantly more time in the target quadrant and less escape latency in the Morris water maze on probe day when compared to the saline-sired ones. The offspring showed significantly less step-through latency to enter the dark compartment compared to the control group when measured in the shuttle box test. Paternal exposure to morphine during adolescence impaired working, novel object recognition, and passive avoidance memory in male offspring. Spatial memory changed in the morphine-sired group compared to the saline-sired one., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: Low frequency stimulation (LFS) inhibits neuronal hyperexcitability following epileptic activity. However, knowledge about LFS' inhibitory mechanisms is lacking. Here, α 1 and α 2 adrenergic receptors' roles in mediating LFS inhibitory action on high-K + induced epileptiform activity (EA) was examined in rat hippocampal slices. Materials and methods: LFS (1 Hz, 900 pulses) was applied to the Schaffer collaterals. Whole-cell, patch clamp recording was used to measure changes in CA1 pyramidal neurons' excitability. By applying high-K + on hippocampal slices, EA was induced, and neuronal excitability increased. Results: When administered at the beginning of EA, LFS reduced neuronal excitability. In the presence of prazosin (10 µM, an α 1 adrenergic receptor antagonist) and yohimbine (5 µM, an α 2 adrenergic receptor antagonist), LFS' typically has a restorative impact on EA-induced membrane potential hyperpolarization and spike firing frequency, but this effect was reduced after high-K + washout; These antagonists did not have a significant effect on LFS' inhibitory action on spike firing during EA. Conclusion: These findings suggest that LFS' anticonvulsant effect, on neuronal hyperexcitability following high-K + EA, may be mediated partly through α adrenergic receptors in hippocampal slices.

Pharmacoresistant temporal lobe epilepsy affects millions of people around the world with uncontrolled seizures and comorbidities, like anxiety, being the most problematic aspects calling for novel therapies. The intrahippocampal kainic acid model of temporal lobe epilepsy is an appropriate rodent model to evaluate the effects of novel interventions, including glycolysis inhibition, on epilepsy-induced alterations. Here, we investigated kainic acid-induced changes in the dorsal hippocampus (dHPC) and basolateral amygdala (BLA) circuit and the efficiency of a glycolysis inhibitor, 2-deoxy D-glucose (2-DG), in resetting such alterations using simultaneous local field potentials (LFP) recording and elevated zero-maze test. dHPC theta and gamma powers were lower in epileptic groups, both in the baseline and anxiogenic conditions. BLA theta power was higher in baseline condition while it was lower in anxiogenic condition in epileptic animals and 2-DG could reverse it. dHPC-BLA coherence was altered only in anxiogenic condition and 2-DG could reverse it only in gamma frequency. This coherence was significantly correlated with the time in which the animals exposed themselves to the anxiogenic condition. Further, theta-gamma phase-locking was lower in epileptic groups in the dHPC-BLA circuit and 2-DG could considerably increase it., (© 2023. The Author(s).)

Objective: The mechanisms behind seizure suppression by deep brain stimulation (DBS) are not fully revealed, and the most optimal stimulus regimens and anatomical targets are yet to be determined. We investigated the modulatory effect of low-frequency DBS (L-DBS) in the ventral tegmental area (VTA) on neuronal activity in downstream and upstream brain areas in chemically kindled mice by assessing c-Fos immunoreactivity., Materials and Methods: In this experimental study, 4-6 weeks old BL/6 male mice underwent stereotaxic implantation of a unilateral stimulating electrode in the VTA followed by pentylenetetrazole (PTZ) administration every other day until they showed stage 4 or 5 seizures following 3 consecutive PTZ injections. Animals were divided into control, sham-implanted, kindled, kindled-implanted, L-DBS, and kindled+L-DBS groups. In the L-DBS and kindled+L-DBS groups, four trains of L-DBS were delivered 5 min after the last PTZ injection. 48 hours after the last L-DBS, mice were transcardially perfused, and the brain was processed to evaluate c-Fos expression by immunohistochemistry., Results: L-DBS in the VTA significantly decreased the c-Fos expressing cell numbers in several brain areas including the hippocampus, entorhinal cortex, VTA, substantia nigra pars compacta, and dorsal raphe nucleus but not in the amygdala and CA3 area of the ventral hippocampus compared to the sham group., Conclusion: These data suggest that the possible anticonvulsant mechanism of DBS in VTA can be through restoring the seizure-induced cellular hyperactivity to normal.

Aims: Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D 2 -like receptors in the antiepileptogenic action of DBS was studied., Methods: Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1 Hz; pulse duration: 0.1 ms; intensity: 50-150 μA; 4 trains of 200 pulses at 5 min intervals). Sulpiride (10 μg/1 μl, i.c.v.), a selective dopamine D 2 -like receptor antagonist, was administered prior to the daily LFS application., Results: Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration., Conclusion: These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D 2 -like (including D 2 , D 3 , and D 4 ) receptors., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABA A subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABA A subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis., (© 2022 Wiley Periodicals LLC.)

Dopamine may be involved in the anticonvulsant action of deep brain stimulation (DBS). Therefore, ventral tegmental area (VTA), as a brain dopaminergic nucleus, may be a suitable target for DBS anticonvulsant action. This study investigated the effect of tonic and phasic stimulations of the VTA on seizure parameters. Seizures were induced in adult mice by sequential injections of a sub-convulsive dose of 35 mg/kg pentylenetetrazole (PTZ) every 48 h to develop the chemical kindling until the mice reached full kindled state (showing three consecutive seizure stages 4 or 5). Fully kindled mice received DBS once a day as tonic (square waves at 1 Hz; pulse duration: 200 μs; intensity: 300 μA; 600 pulses in 10 min) or phasic (square waves at 100 Hz; pulse duration: 200 μs; intensity: 300 μA; 8 trains of 10 pulses at 1 min interval; 800 pulses in 10 min) stimulations applied into their VTA for 4 days. A single dose of PTZ was injected after each DBS. Simultaneously electrocorticography and video recordings were performed during the seizure for accuracy in seizure severity parameters detection. Tonic but not phasic stimulation significantly decreased the epileptiform discharge duration and the seizure behavioral parameters such as maximum seizure stage, stage 5 duration, seizure duration. In addition, focal to generalized seizure latency increased following VTA tonic stimulation. These data suggest that tonic (but not phasic) stimulation of VTA before PTZ injection on 4 test days had anticonvulsant effects on PTZ-kindled seizures., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Temporal lobe epilepsy is the most drug-resistant type with the highest incidence among the other focal epilepsies. Metabolic manipulations are of great interest among others, glycolysis inhibitors like 2-deoxy D-glucose (2-DG) being the most promising intervention. Here, we sought to investigate the effects of 2-DG treatment on cellular and circuit level electrophysiological properties using patch-clamp and local field potentials recordings and behavioral alterations such as depression and anxiety behaviors, and changes in nitric oxide signaling in the intrahippocampal kainic acid model. We found that epileptic animals were less anxious, more depressed, with more locomotion activity. Interestingly, by masking the effect of increased locomotor activity on the parameters of the zero-maze test, no altered anxiety behavior was noted in epileptic animals. However, 2-DG could partially reverse the behavioral changes induced by kainic acid. The findings also showed that 2-DG treatment partially suppresses cellular level alterations while failing to reverse circuit-level changes resulting from kainic acid injection. Analysis of NADPH-diaphorase positive neurons in the CA1 area of the hippocampus revealed that the number of positive neurons was significantly reduced in dorsal CA1 of the epileptic animals and 2-DG treatment did not affect the diminishing effect of kainic acid on NADPH-d + neurons in the CA1 area. In the control group receiving 2-DG, however, an augmented NADPH-d + cell number was noted. These data suggest that 2-DG cannot suppress epileptiform activity at the circuit-level in this model of epilepsy and therefore, may fail to control the seizures in temporal lobe epilepsy cases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Low frequency deep brain electrical stimulation (LFS) is a potential therapeutic strategy to control seizures in epilepsy patients. Given the functional connection of the olfactory bulb with the hippocampal formation, in this study the effect of applying LFS in the olfactory bulb on seizure severity, and learning and memory was investigated in hippocampal kindling. In male Wistar rats (250-300 g), a tripolar electrode was inserted in the CA1 region of the right hippocampus to apply kindling stimulations and record the afterdischarges (ADs). Two bipolar electrodes were also inserted bilaterally into the olfactory bulbs for applying LFS. In the kindled group, the animals received daily kindling stimulations to produce stage 5 seizures for three consecutive days. In one group of subjects, LFS was administered 2-3 min after the last kindling stimulation. Within this group, subjects were divided into two subgroups: one subgroup received two and the other subgroup received four packages of LFS protocol. Obtained data showed that bilateral LFS application to the left and right olfactory bulb reduced seizure severity. Among the protocols, applying four packages of LFS had a greater anticonvulsant effect compared to applying two packages LFS. Applying LFS in the olfactory bulb of kindled subject restored performance on measures that test short- and long-term memory - the Y maze and Morris water maze test - and applying four packages of LFS was more effective than two. These results indicated that applying LFS to the olfactory bulb had anticonvulsant effects and ameliorated the seizure-induced impairment of working and spatial memory. These effects appear to be depended on the number of applied LFS and were greater by increasing the number of LFS., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)