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A 65-years-old female was hospitalized 24 h after experiencing the sudden onset of subjective reduction in visual acuity and hypersomnia. On admission to the neurological ward, she presented isolated downgaze palsy. A Magnetic Resonance Imaging of the brain disclosed a discrete, ovalar hyperintensity involving the left paramedian thalamic-mesencephalon junction. The lesion was consistent with infarction. Isolated downgaze palsy has been described in thrombosis of Artery of Percheron leading to infarction of bilateral paramedian thalami along with structures from the mesencephalic-diencephalic junction such as the Medial Longitudinal Fasciculus (riMLF). While neurons from the riMLF controlling upward vertical saccades project to either ipsilateral and contralateral oculomotor nuclear complexes, those involved in regulating downgaze descend ipsilaterally in the brain stem. Isolated downgaze palsy has an extreme localizer value to the diencephalic-mesencephalon junction and can arise from a unilateral lesion.

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PURPOSE: The thalamo-mesencephalic (TM) branches of the posterior cerebral artery (PCA) supply critical structures. Previous descriptions of these vessels are inconsistent and almost exclusively rely on cadaver studies. We aimed to provide a neuroradiological description of TM vessels in vivo based on routine 3D rotational angiographies (3D-RA). METHODS: We analyzed 3D-RAs of 58 patients with pathologies remote from the PCA. PCA-origins were considered. Delineation, origin and number of branches of the collicular artery (CA), the accessory CA (ACA), the posterior thalamoperforating artery (PTA), the thalamogeniculate artery (TGA), and the posterior medial (PMCA) and lateral (PCLA) choroid arteries were assessed. The PTAs were categorized based on Percheron's suggested classification. RESULTS: A CA was identified in 84%, an ACA in 20%. The PTA was delineated in 100%. In 27%, PTA anatomy had features of several Percheron types (n = 7) or vessels emanating from a net like origin (n = 9). 26% had a type IIb PTA. A fetal type PCA origin with hypoplastic ipsilateral P1 was observed in 5 cases with type IIa (n = 2) or type IIb (n = 3) PTAs originating from contralateral P1. The TGA was identified in 85% of patients, with ≥ 2 branches in 67%. The PMCA was delineable in 41%, the PLCA in 100%. CONCLUSION: The prevalence of a proper "Artery of Percheron" type IIb PTA seems to be higher than previously reported. A fetal type P1-origin may be predictive of a type IIa/b PTA emanating from contralateral P1. 3D-RA may be useful for planning PCA interventions, as impairment of TM branches is a severe risk.

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In black porgy (Acanthopagrus schlegelii), the brain-pituitary-testis (Gnrh-Gths-Dmrt1) axis plays a vital role in male fate determination and maintenance, and then inhibiting female development in further (puberty). However, the feedback of gonadal hormones on regulating brain signaling remains unclear. In this study, we conducted short-term sex steroid treatment and surgery of gonadectomy to evaluate the feedback regulation between the gonads and the brain. The qPCR results show that male phase had the highest gths transcripts; treatment with estradiol-17ß (E2) or 17α-methyltestosterone (MT) resulted in the increased pituitary lhb transcripts. After surgery, apart from gnrh1, there is no difference in brain signaling genes between gonadectomy and sham fish. In the diencephalon/mesencephalon transcriptome, de novo assembly generated 283,528 unigenes; however, only 443 (0.16%) genes showed differentially expressed between sham and gonadectomy fish. In the present study, we found that exogenous sex steroids affect the gths transcription; this feedback control is related to the gonadal stage. Furthermore, gonadectomy may not affect gene expression of brain signaling (Gnrh-Gths axis). Our results support the communication between ovotestis and brain signaling (Gnrh-Gths-testicular Dmrt1) for the male fate.

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OBJECTIVE: The authors report on a large, consecutive, single-surgeon series of patients undergoing microsurgical removal of midbrain gliomas. Emphasis is put on surgical indications, technique, and results as well as long-term oncological follow-up. METHODS: A retrospective analysis was performed of prospectively collected data from a consecutive series of patients undergoing microneurosurgery for midbrain gliomas from March 2006 through June 2022 at the authors' institution. According to the growth pattern and location of the lesion in the midbrain (tegmentum, central mesencephalic structures, and tectum), one of the following approaches was chosen: transsylvian (TS), extreme anterior interhemispheric transcallosal (eAIT), posterior interhemispheric transtentorial subsplenial (PITS), paramedian supracerebellar transtentorial (PST), perimedian supracerebellar (PeS), perimedian contralateral supracerebellar (PeCS), and transuvulotonsillar fissure (TUTF). Clinical and radiological data were gathered according to a standard protocol and reported according to common descriptive statistics. The main outcomes were rate of gross-total resection; extent of resection; occurrence of any complications; variation in Karnofsky Performance Status score at discharge, 3 months, and last follow-up; progression-free survival (PFS); and overall survival (OS). RESULTS: Fifty-four patients (28 of them pediatric) met the inclusion criteria (6 with high-grade and 48 with low-grade gliomas [LGGs]). Twenty-two tumors were in the tegmentum, 7 in the central mesencephalic structures, and 25 in the tectum. In no instance did the glioma originate in the cerebral peduncle. TS was performed in 2 patients, eAIT in 6, PITS in 23, PST in 16, PeS in 4, PeCS in 1, and TUTF in 2 patients. Gross-total resection was achieved in 39 patients (72%). The average extent of resection was 98.0% (median 100%, range 82%-100%). There were no deaths due to surgery. Nine patients experienced transient and 2 patients experienced permanent new neurological deficits. At a mean follow-up of 72 months (median 62, range 3-193 months), 49 of the 54 patients were still alive. All patients with LGGs (48/54) were alive with no decrease in their KPS score, whereas 42 showed improvement compared with their preoperative status. CONCLUSIONS: Microneurosurgical removal of midbrain gliomas is feasible with good surgical results and long-term clinical outcomes, particularly in patients with LGGs. As such, microneurosurgery should be considered as the first therapeutic option. Adequate microsurgical technique and anesthesiological management, along with an accurate preoperative understanding of the tumor's exact topographic origin and growth pattern, is crucial for a good surgical outcome.

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INTRODUCTION: Due to the important functions of the mesencephalon, knowledge of its morphometric characteristics in a healthy population is important for any pathological diagnosis. The aim of this study was to determine the specific morphometric values of the mesencephalon in a healthy Turkish population. METHODS: Magnetic resonance (MR) images of 184 subjects (98 females, 86 males) with a mean age of 47.33 years (range 18 to 85 years) were included in the study. Then, parameter measurements were performed on 1.5 T MR images, and MicroDicom Digital Imaging and Communications in Medicine (DICOM) viewer 2022.1 (MicroDicom Ltd., Sofia, Bulgaria) software program was used for the measurements. RESULTS: The mean sagittal diameter of the right cerebral peduncle was 17.17±2.03 mm, the mean cross-sectional area of the right cerebral peduncle was 171.75±32.81 mm2, the mean transverse diameter of the left cerebral peduncle was 16.60±2.32 mm, sagittal diameter of tectum and tegmentum 17.01±1.57 mm, the cross-sectional area of tectum and tegmentum 223.40±27.37 mm2 and pontomesencephalic angle 52.03°±10.61°, while in males these values were 18.26±2.38 mm, 182.61±38.57 mm2, 17.39±2.57 mm, 17.76±1.90 mm, 237.20±35.94 mm2 and 56.77°±9.78°, respectively. Except for the mamillopontine distance, there was a statistically significant difference between genders in the other parameters (p<0.05). CONCLUSION: In conclusion, the findings related to the mesencephalon obtained in this study are presented for the first time in a healthy Turkish population. Especially, the cerebral peduncle cross-sectional area, tectum and tegmentum cross-sectional area, and cerebral peduncle transverse diameter can be evaluated clinically. We believe that knowledge of these values will guide specialists and radiologists in the diagnosis of any pathologic condition. Furthermore, the pontomesencephalic angle and mamillopontine distance have been identified as potentially useful landmarks in the diagnosis of intracranial hypotension and hydrocephalus. In particular, these angles can be measured in patient groups and may be a potential landmark in making an alternative diagnosis.

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The locked-in syndrome (LiS) is defined as the loss of most voluntary muscle movements with preserved cognitive abilities due to a ventral pontine lesion. However, some patients may also have severe impairment of consciousness [locked-in plus syndrome (LiPS)]. Here we aimed to explore structural differences between LiS and LiPS patients of vascular aetiology, focusing on lesion patterns and locations to better delineate the clinical spectrum of LiS and LiPS. In this retrospective case series study, we report nine patients (two women), ages 29-74 years (median 50) with LiS and LiPS who were diagnosed between 2007 and 2021. Clinical parameters, MRI findings including the lesioned structures, and a shape feature calculation are presented for every patient. The lesioned structures were determined by a senior neuroradiologist. Two of nine patients had fully retained consciousness (LiS) and seven showed various degrees of impaired consciousness (LiPS). Lesions of LiS patients are round and confined to the pons, whereas lesions of LiPS patients are more elongated and reach neighbouring areas such as the mesencephalon, thalamus or ascending reticular activating system. Lesions involving the mesencephalon and the thalamus are strong indicators of LiPS, whereas for lesions restricted to the pons, the dorsal extension and the associated damage to the ascending reticular activating system are crucial to differentiate LiS from LiPS. Recognizing LiPS using clinical and radiological findings is important as these patients may need different therapies and care and, most importantly, should not be mistaken as unresponsive wakefulness syndrome.

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Previous studies showed that the dorsal premammillary nucleus of the hypothalamus (PMD) is involved in social passive defensive behaviors likely to be meditated by descending projections to the periaqueductal gray (PAG). We focused on the rostral dorsomedial PAG (rPAGdm) to reveal its putative neural mechanisms involved in mediating social defensive responses. By combining retrograde tracing and FOS expression analysis, we showed that in addition to the PMD, the rPAGdm is influenced by several brain sites active during social defeat. Next, we found that cytotoxic lesions of the rPAGdm drastically reduced passive defense and did not affect active defensive responses. We then examined the rPAGdm's projection pattern and found that the PAGdm projections are mostly restricted to midbrain sites, including the precommissural nucleus, different columns of the PAG, and the cuneiform nucleus (CUN). Also, we found decreased FOS expression in the caudal PAGdm, CUN, and PMD after the rPAGdm was lesioned. The results support that the rPAGdm mediates passive social defensive responses through ascending paths to prosencephalic circuits likely mediated by the CUN. This study provides further support for the role of the PAG in the modulation of behavioral responses by working as a unique hub for influencing prosencephalic sites during the mediation of aversive responses.

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Wernekink commissure syndrome (WCS) is an extremely rare midbrain syndrome, in which there is the selective destruction of the decussation of the superior cerebellar peduncle, which commonly presents with bilateral cerebellar signs. We describe a case of WCS with Holmes tremor in a patient having an undiagnosed involuntary movement disorder since childhood following an undocumented case of meningitis. The patient presented with sudden onset gait instability with bilateral cerebellar signs (more prominent on the left side), Holmes tremor in bilateral limbs, slurred speech, and marked dysarthria. No ophthalmoplegia or palatal tremors were noted. The patient was conservatively managed along the lines of a stroke, and there was a marked improvement in cerebellar signs and Holmes tremor with time but no evolution (improvement or worsening) was observed in the involuntary movements of limbs and face that were present before the onset of WCS.

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OBJECTIVE: The nature of neurovascular involvement in cases of familial Mediterranean fever (FMF) has not been adequately clarified. METHODS AND PATIENTS: Clinical features, infarct topography, vascular status, and stroke etiology were prospectively determined in 35 acute neurovascular events that occurred in 23 FMF patients. Clinicoradiological features were compared with an age- and gender-matched control group of 115 acute stroke patients. Characteristics of additional FMF and acute stroke cases (6 episodes in 6 patients) identified from a systematic literature review (PROSPERO registration no: CRD420212264820) were also analyzed. RESULTS: There were 27 acute ischemic stroke episodes in 19 patients, 7 transient ischemic attack episodes in 3 patients, and 1 patient with a single episode of parietal hematoma in our cohort. Twenty (74%) ischemic stroke episodes in 12 patients were cryptogenic. Ten of these 12 cases had a previous FMF diagnosis and were taking colchicine. There was no significant difference in the FMF group in terms of the presence of vascular risk factors and angiography-documented disease in comparison to controls. Cerebral distal artery involvement was significantly prevalent in FMF (78% vs 45%, P = .002). Especially, midbrain central deep perforating territory involvement was higher (30% vs 1%, P < .001). The long-term prognosis (median 8.5 years) under antiplatelet agents and colchicine is favorable. DISCUSSION: The acute stroke phenotype in FMF cases is herein described for the first time. Several clinicoradiological features such as thrombotic lacunar infarcts located in the central mesencephalon seem so typical that we recommend searching for FMF mutations in geographic regions where FMF is common.

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Parkinson's Disease (PD) is a prevalent neurodegenerative disorder that is characterized pathologically by the loss of A9-specific dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD is currently unresolved, and the disease remains incurable. This, in part, is due to the lack of an experimental disease model that could faithfully recapitulate the features of human PD. However, the recent advent of induced pluripotent stem cell (iPSC) technology has allowed PD models to be created from patient-derived cells. Indeed, DA neurons from PD patients are now routinely established in many laboratories as monolayers as well as 3D organoid cultures that serve as useful toolboxes for understanding the mechanism underlying PD and also for drug discovery. At the same time, the iPSC technology also provides unprecedented opportunity for autologous cell-based therapy for the PD patient to be performed using the patient's own cells as starting materials. In this review, we provide an update on the molecular processes underpinning the development and differentiation of human pluripotent stem cells (PSCs) into midbrain DA neurons in both 2D and 3D cultures, as well as the latest advancements in using these cells for drug discovery and regenerative medicine. For the novice entering the field, the cornucopia of differentiation protocols reported for the generation of midbrain DA neurons may seem daunting. Here, we have distilled the essence of the different approaches and summarized the main factors driving DA neuronal differentiation, with the view to provide a useful guide to newcomers who are interested in developing iPSC-based models of PD.

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We report a case of fetal diencephalic-mesencephalic junction dysplasia (DMJD) diagnosed prenatally. Prenatal ultrasound at 24 gestational weeks showed that the fetus was small, about the size at 22 weeks' gestation, with short biparietal diameter and enhanced echo at the anterior border of thalamus. Fetal MRI showed short T2 signal shadow in the left choroid plexus, and hemorrhage and midbrain dysplasia were suspected. A pathogenic homozygous mutation variant in protocadherins 12 gene (c.1558C>T) was found in this fetus by whole exome sequencing and both parents carried the same heterozygous variation revealed by Sanger sequencing. All of the above information lead to the diagnosis of fetal DMJD, and the pregnancy was terminated after genetic counseling.

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Benedikt syndrome is a rare neurological disorder of the midbrain. Herein, we present a case of Benedikt syndrome, who presented with left-sided body weakness, right oculomotor nerve palsy, cerebellar ataxia, and Holmes tremor in the left upper limb following midbrain infarction. She was treated with aspirin, clopidogrel, and amiodarone.

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This is the first study aiming to develop a method for the long-term visualization of living nigrostriatal dopaminergic neurons using 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine-BODIPY (GBR-BP), the original fluorescent substance, which is a derivative of GBR-12909, a dopamine uptake inhibitor. This method is based on the authors' hypothesis about the possibility of specifically internalizing into dopaminergic neurons substances with a high affinity for the dopamine transporter (DAT). Using a culture of mouse embryonic mesencephalic and LUHMES cells (human embryonic mesencephalic cells), as well as slices of the substantia nigra of adult mice, we have obtained evidence that GBR-BP is internalized specifically into dopaminergic neurons in association with DAT via a clathrin-dependent mechanism. Moreover, GBR-BP has been proven to be nontoxic. As we have shown in a primary culture of mouse metencephalon, GBR-BP is also specifically internalized into some noradrenergic and serotonergic neurons, but is not delivered to nonmonoaminergic neurons. Our data hold great promise for visualization of dopaminergic neurons in a mixed cell population to study their functioning, and can also be considered a new approach for the development of targeted drug delivery to dopaminergic neurons in pathology, including Parkinson's disease.

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Locomotion exists in diverse forms in nature; however, little is known about how closely related species with similar neuronal circuitry can evolve different navigational strategies to explore their environments. Here, we investigate this question by comparing divergent swimming pattern in larval Danionella cerebrum (DC) and zebrafish (ZF). We show that DC displays long continuous swimming events when compared with the short burst-and-glide swimming in ZF. We reveal that mesencephalic locomotion maintenance neurons in the midbrain are sufficient to cause this increased swimming. Moreover, we propose that the availability of dissolved oxygen and timing of swim bladder inflation drive the observed differences in the swim pattern. Our findings uncover the neural substrate underlying the evolutionary divergence of locomotion and its adaptation to their environmental constraints.

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The degeneration of dopaminergic and other neurons in the aging brain is considered a process starting well beyond the infantile and juvenile period. In contrast to other dopamine-associated neuropsychiatric disorders, such as schizophrenia and drug addiction, typically diagnosed during adolescence or young adulthood and, thus, thought to be rooted in the developing brain, Parkinson's Disease (PD) is rarely viewed as such. However, evidences have accumulated suggesting that several factors might contribute to an increased vulnerability to death of the dopaminergic neurons at an already very early (developmental) phase in life. Despite the remarkable ability of the brain to compensate such dopamine deficits, the early loss or dysfunction of these neurons might predispose an individual to suffer from PD because the critical threshold of dopamine function will be reached much earlier in life, even if the time-course and strength of naturally occurring and age-dependent dopaminergic cell death is not markedly altered in this individual. Several signaling and transcriptional pathways required for the proper embryonic development of the midbrain dopaminergic neurons, which are the most affected in PD, either continue to be active in the adult mammalian midbrain or are reactivated at the transition to adulthood and under neurotoxic conditions. The persistent activity of these pathways often has neuroprotective functions in adult midbrain dopaminergic neurons, whereas the reactivation of silenced pathways under pathological conditions can promote the survival and even regeneration of these neurons in the lesioned or aging brain. This article summarizes our current knowledge about signaling and transcription factors involved in midbrain dopaminergic neuron development, whose reduced gene dosage or signaling activity are implicated in a lower survival rate of these neurons in the postnatal or aging brain. It also discusses the evidences supporting the neuroprotection of the midbrain dopaminergic system after the external supply or ectopic expression of some of these secreted and nuclear factors in the adult and aging brain. Altogether, the timely monitoring and/or correction of these signaling and transcriptional pathways might be a promising approach to a much earlier diagnosis and/or prevention of PD.

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The similarities between amphioxus and vertebrate brains, in their regional subdivision, cell types and circuitry, make the former a useful benchmark for understanding the evolutionary innovations that shaped the latter. Locomotory control systems were already well developed in basal chordates, with the ventral neuropile of the dien-mesencephalon serving to set levels of activity and initiate locomotory actions. A chief deficit in amphioxus is the absence of complex vertebrate-type sense organs. Hence, much of vertebrate story is one of progressive improvement both to these and to sensory experience more broadly. This has two aspects: (i) anatomical and neurocircuitry innovations in the organs of special sense and the brain centres that process and store their output, and (ii) the emergence of primary consciousness, i.e. sentience. With respect to the latter, a bottom up, evolutionary perspective has a different focus from a top down human-centric one. At issue: the obstacles to the emergence of sentience in the first instance, the sequence of addition of new contents to evolving consciousness, and the homology relationship between them. A further question, and a subject for future investigation, is how subjective experience is optimized for each sensory modality. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

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OBJECTIVE: Anatomical taxonomy is a practical tool that has successfully guided clinical decision-making for patients with brain arteriovenous malformations. Brainstem cavernous malformations (BSCMs) are similarly complex lesions that are difficult to access and highly variable in size, shape, and position. The authors propose a novel taxonomy for midbrain cavernous malformations based on clinical presentation (syndromes) and anatomical location (identified with MRI). METHODS: The taxonomy system was developed and applied to an extensive 2-surgeon experience over a 30-year period (1990-2019). Of 551 patients with appropriate data who underwent microsurgical resection of BSCMs, 151 (27.4%) had midbrain lesions. These lesions were further subtyped on the basis of predominant surface presentation identified on preoperative MRI. Five distinct subtypes of midbrain BSCMs were defined: interpeduncular (7 lesions [4.6%]), peduncular (37 [24.5%]), tegmental (73 [48.3%]), quadrigeminal (27 [17.9%]), and periaqueductal (7 [4.6%]). Neurological outcomes were assessed using modified Rankin Scale (mRS) scores. A postoperative score ≤ 2 was defined as a favorable outcome; a score > 2 was defined as a poor outcome. Clinical and surgical characteristics and neurological outcomes were compared among subtypes. RESULTS: Each midbrain BSCM subtype was associated with a recognizable constellation of neurological symptoms. Patients with interpeduncular lesions commonly presented with ipsilateral oculomotor nerve palsy and contralateral cerebellar ataxia or dyscoordination. Peduncular lesions were associated with contralateral hemiparesis and ipsilateral oculomotor nerve palsy. Patients with tegmental lesions were the most likely to present with contralateral sensory deficits, whereas those with quadrigeminal lesions commonly presented with the features of Parinaud syndrome. Periaqueductal lesions were the most likely to cause obstructive hydrocephalus. A single surgical approach was preferred (> 90% of cases) for each midbrain subtype: interpeduncular (transsylvian-interpeduncular approach [7/7 lesions]), peduncular (transsylvian-transpeduncular [24/37]), tegmental (lateral supracerebellar-infratentorial [73/73]), quadrigeminal (midline or paramedian supracerebellar-infratentorial [27/27]), and periaqueductal (transcallosal-transchoroidal fissure [6/7]). Favorable outcomes (mRS score ≤ 2) were observed in most patients (110/136 [80.9%]) with follow-up data. No significant differences in outcomes were observed between subtypes (p = 0.92). CONCLUSIONS: The study confirmed the authors' hypothesis that taxonomy for midbrain BSCMs can meaningfully guide the selection of surgical approach and resection strategy. The proposed taxonomy can increase diagnostic acumen at the patient bedside, help identify optimal surgical approaches, enhance the consistency of clinical communications and publications, and improve patient outcomes.

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INTRODUCTION: Midbrain dopaminergic neurons are involved in various brain functions, including motor behavior, reinforcement, motivation, learning, and cognition. Primary dopaminergic neurons and also several lines of these cells are extensively used in cell culture studies. Primary dopaminergic neurons prepared from rodents have been cultured in both DMEM/F12 and neurobasal mediums in several studies. However, there is no document reporting the comparison of these two mediums. So in this study, we evaluated the neurons and astroglial cells in primary midbrain neurons from rat embryos cultured in DMEM/F12 and neurobasal mediums. METHODS: Primary mesencephalon cells were prepared from the E14.5 rat embryo. Then they were seeded in two different mediums (Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 [DMEM/F12] and neurobasal). On day 3 and day 5, half of the medium was replaced with a fresh medium. On day 7, ß3-tubulin-, GFAP (Glial fibrillary acidic protein)- and Tyrosine Hydroxylase TH-positive cells were characterized as neurons, astrocytes, and dopaminergic neurons, respectively, using immunohistochemistry. Furthermore, the morphology of the cells in both mediums was observed under light microscopy on days 1, 3, and 5. RESULTS: The cells cultured in both mediums were similar under light microscopy regarding the cell number, but in a neurobasal medium, the cells have aggregated and formed clustering structures. Although GFAP-immunoreactive cells were lower in neurobasal compared to DMEM/F12, the number of ß3-tubulin- and TH-positive cells in both cultures was the same. CONCLUSION: This study's findings demonstrated that primary midbrain cells from the E14.5 rat embryo could grow in both DMEM/F12 and neurobasal mediums. Therefore, considering the high price of a neurobasal medium, it can be replaced with DMEM/F12 for culturing primary dopaminergic neurons.

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Dysfunctional coping styles are involved in the development, persistence, and relapse of psychiatric diseases. Passive coping with stress challenges (helplessness) is most commonly used in animal models of dysfunctional coping, although active coping strategies are associated with generalized anxiety disorder, social anxiety disorder, panic, and phobias as well as obsessive-compulsive and post-traumatic stress disorder. This paper analyzes the development of dysfunctional active coping strategies of mice of the helplessness-resistant DBA/2J (D2) inbred strain, submitted to temporary reduction in food availability in an uncontrollable and unavoidable condition. The results indicate that food-restricted D2 mice developed a stereotyped form of food anticipatory activity and dysfunctional reactive coping in novel aversive contexts and acquired inflexible and perseverant escape strategies in novel stressful situations. The evaluation of FosB/DeltaFosB immunostaining in different brain areas of food-restricted D2 mice revealed a pattern of expression typically associated with behavioral sensitization to addictive drugs and compulsivity. These results support the conclusion that an active coping style represents an endophenotype of mental disturbances characterized by perseverant and inflexible behavior.

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Midbrain dopaminergic neurons (mDA) play an important role in controlling the voluntary motor movement, reward, and emotion-based behaviour. Differentiation of mDA neurons from progenitors depends on several secreted proteins, such as sonic hedgehog (SHH). The present study attempted to elucidate the possible role(s) of some SHH signaling components (Ptch1, Gli1, Gli2 and Gli3) in the spatiotemporal development of mDA neurons along the rostrocaudal axis of the midbrain and their possible roles in differentiation and survival of mDA neurons and the significance of using in vitro models for studying the development of mDA neurons. At E12 and E14, only Ptch1 and Gli1 were expressed in ventrolateral midbrain domains. All examined SHH signalling molecules were not detected in mDA area. Whereas, in MN9D cells, many SHH signalling molecules were expressed and co-localized with the dopaminergic marker; tyrosine hydroxylase (TH), and their expression were upregulated with SHH treatment of the MN9D cells. These results suggest that mDA neurons differentiation and survival might be independent of SHH in the late developmental stages (E12-18). Besides, MN9D cell line is not the ideal in vitro model for investigating the differentiation of mDA and hence, the ventral midbrain primary culture might be favored over MN9D line.

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