Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700
Brain Sciences brainsci	2.7	4.8	2011	15.6 Days	CHF 2200
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900

16 pages, 582 KiB

Open AccessReview

Advancing Obsessive–Compulsive Disorder Research: Insights from Transgenic Animal Models and Innovative Therapies

by Xinyuejia Huang, Linglong Xiao, Mengqi Wang, Yang Wu, Hao Deng and Wei Wang

Brain Sci. 2025, 15(1), 43; https://doi.org/10.3390/brainsci15010043 - 4 Jan 2025

Viewed by 1570

Obsessive–compulsive disorder (OCD) is a prevalent, chronic, and severe neuropsychiatric disorder that leads to illness-related disability. Despite the availability of several treatments, many OCD patients respond inadequately, because the underlying neural mechanisms remain unclear, necessitating the establishment of many animal models, particularly mouse [...] Read more.

Obsessive–compulsive disorder (OCD) is a prevalent, chronic, and severe neuropsychiatric disorder that leads to illness-related disability. Despite the availability of several treatments, many OCD patients respond inadequately, because the underlying neural mechanisms remain unclear, necessitating the establishment of many animal models, particularly mouse models, to elucidate disease mechanisms and therapeutic strategies better. Although the development of animal models is ongoing, there remain many comprehensive summaries and updates in recent research, hampering efforts to develop novel treatments and enhance existing interventions. This review summarizes the phenotypes of several commonly used models and mechanistic insights from transgenic models of OCD, such as knockout mouse models. In addition, we present the advantages and limitations of these models and discuss their future in helping further understand the pathophysiology and advanced treatment. Here, we highlight current frontline treatment approaches for OCD, including neuromodulation and surgical interventions, and propose potential future directions. By studying gene mutations and observing phenotypes from available OCD animal models, researchers have classified the molecular signatures of each model reminiscent of changes in brain areas and neural pathways, with the hope of guiding the future selection of the most appropriate models for specific research in the OCD field. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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33 pages, 4365 KiB

Open AccessArticle

Unravelling Secondary Brain Injury: Insights from a Human-Sized Porcine Model of Acute Subdural Haematoma

by Thomas Kapapa, Vanida Wernheimer, Andrea Hoffmann, Tamara Merz, Fabia Zink, Eva-Maria Wolfschmitt, Oscar McCook, Josef Vogt, Martin Wepler, David Alexander Christian Messerer, Claire Hartmann, Angelika Scheuerle, René Mathieu, Simon Mayer, Michael Gröger, Nicole Denoix, Enrico Clazia, Peter Radermacher, Stefan Röhrer and Thomas Datzmann

Cells 2025, 14(1), 17; https://doi.org/10.3390/cells14010017 - 27 Dec 2024

Viewed by 1511

Abstract

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure [...] Read more.

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure (ICP), cerebral perfusion pressure (CPP) or decompressive craniectomy improve patient outcome remain partly unanswered. Experimental drug approaches for the treatment of secondary brain injury (SBI) have not found clinical application. The complex, cellular and molecular pathways of SBI remain incompletely understood, and there are insufficient experimental (animal) models that reflect the pathophysiology of human TBI to develop translational therapeutic approaches. Therefore, we investigated different injury patterns after acute subdural hematoma (ASDH) as TBI in a post-hoc approach to assess the impact on SBI in a long-term, human-sized porcine TBI animal model. Post-mortem brain tissue analysis, after ASDH, bilateral ICP, CPP, cerebral oxygenation and temperature monitoring, and biomarker analysis were performed. Extracerebral, intraparenchymal–extraventricular and intraventricular blood, combined with brainstem and basal ganglia injury, influenced the experiment and its outcome. Basal ganglia injury affects the duration of the experiment. Recognition of these different injury patterns is important for translational interpretation of results in this animal model of SBI after TBI. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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23 pages, 3455 KiB

Open AccessArticle

Efficient and Accurate Brain Tumor Classification Using Hybrid MobileNetV2–Support Vector Machine for Magnetic Resonance Imaging Diagnostics in Neoplasms

by Mohammed Jajere Adamu, Halima Bello Kawuwa, Li Qiang, Charles Okanda Nyatega, Ayesha Younis, Muhammad Fahad and Salisu Samaila Dauya

Brain Sci. 2024, 14(12), 1178; https://doi.org/10.3390/brainsci14121178 - 25 Nov 2024

Cited by 1 | Viewed by 1830

Abstract

Background/Objectives: Magnetic Resonance Imaging (MRI) plays a vital role in brain tumor diagnosis by providing clear visualization of soft tissues without the use of ionizing radiation. Given the increasing incidence of brain tumors, there is an urgent need for reliable diagnostic tools, as [...] Read more.

Background/Objectives: Magnetic Resonance Imaging (MRI) plays a vital role in brain tumor diagnosis by providing clear visualization of soft tissues without the use of ionizing radiation. Given the increasing incidence of brain tumors, there is an urgent need for reliable diagnostic tools, as misdiagnoses can lead to harmful treatment decisions and poor outcomes. While machine learning has significantly advanced medical diagnostics, achieving both high accuracy and computational efficiency remains a critical challenge. Methods: This study proposes a hybrid model that integrates MobileNetV2 for feature extraction with a Support Vector Machine (SVM) classifier for the classification of brain tumors. The model was trained and validated using the Kaggle MRI brain tumor dataset, which includes 7023 images categorized into four types: glioma, meningioma, pituitary tumor, and no tumor. MobileNetV2’s efficient architecture was leveraged for feature extraction, and SVM was used to enhance classification accuracy. Results: The proposed hybrid model showed excellent results, achieving Area Under the Curve (AUC) scores of 0.99 for glioma, 0.97 for meningioma, and 1.0 for both pituitary tumors and the no tumor class. These findings highlight that the MobileNetV2-SVM hybrid not only improves classification accuracy but also reduces computational overhead, making it suitable for broader clinical use. Conclusions: The MobileNetV2-SVM hybrid model demonstrates substantial potential for enhancing brain tumor diagnostics by offering a balance of precision and computational efficiency. Its ability to maintain high accuracy while operating efficiently could lead to better outcomes in medical practice, particularly in resource limited settings. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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16 pages, 1928 KiB

Open AccessArticle

Knocking Out TAAR5: A Pathway to Enhanced Neurogenesis and Dopamine Signaling in the Striatum

by Anastasia N. Vaganova, Zoia S. Fesenko, Evgeniya V. Efimova, Sergei A. Chekrygin, Daria D. Shafranskaya, Andrey D. Prjibelski, Nataliia V. Katolikova and Raul R. Gainetdinov

Cells 2024, 13(22), 1910; https://doi.org/10.3390/cells13221910 - 19 Nov 2024

Viewed by 1422

Abstract

The member of trace-amine associated receptor family, TAAR5 receptor was suggested to recognize tertiary amines, mostly in the olfactory system; however, knocking out the receptor TAAR5 in mice showed an enhancing effect on adult neurogenesis and dopamine neurotransmission in the striatum. To estimate [...] Read more.

The member of trace-amine associated receptor family, TAAR5 receptor was suggested to recognize tertiary amines, mostly in the olfactory system; however, knocking out the receptor TAAR5 in mice showed an enhancing effect on adult neurogenesis and dopamine neurotransmission in the striatum. To estimate the role of the TAAR5, we performed gene expression profiling of striatal samples from TAAR5 knockout (KO) mice and their wild-type littermates. The higher expression of several genes involved in dopaminergic signaling and the downregulation of genes associated with gliogenesis were revealed in TAAR5-KO mice. Meanwhile, the upregulating effect of TAAR5 knockout on genes was associated with neurogenesis and synaptogenesis. The estimation of cell-type relative abundance through the deconvolution of RNA sequencing data demonstrated that TAAR5-KO striatum samples contain more D2 dopamine receptor-expressing medium spiny neurons but fewer astrocytes than wild-type mice. Our findings indicate that previously identified improvement in cognitive functions and motor coordination in TAAR5-KO mice may activate genes involved in neurogenesis, synaptogenesis, and synapse organization in the striatum. These data suggest that the pharmaceutical targeting of TAAR5 may improve striatum-dependent cognitive or motor functions. At the same time, a more detailed investigation of future TAAR5 antagonists’ effect on glia development is necessary. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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22 pages, 4136 KiB

Open AccessArticle

Biosafety Evaluation of a Chimeric Adenoviral Vector in Mini-Pigs: Insights into Immune Tolerance and Gene Therapy Potential

by Andrei Izmailov, Irina Minyazeva, Vage Markosyan, Zufar Safiullov, Ilnaz Gazizov, Ilnur Salafutdinov, Maria Markelova, Ravil Garifulin, Maksim Shmarov, Denis Logunov, Rustem Islamov and Vadim Pospelov

Biomedicines 2024, 12(11), 2568; https://doi.org/10.3390/biomedicines12112568 - 9 Nov 2024

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Abstract

Background: The biosafety of gene therapy products remains a major challenge to their introduction into the clinic. In particular, the problem of immunogenicity of viral vectors is the focus of attention. Large animals such as pigs, whose anatomical and physiological characteristics are similar [...] Read more.

Background: The biosafety of gene therapy products remains a major challenge to their introduction into the clinic. In particular, the problem of immunogenicity of viral vectors is the focus of attention. Large animals such as pigs, whose anatomical and physiological characteristics are similar to those of humans, have an advantage in testing vector systems. Methods: We performed a comprehensive in vitro and in vivo study to evaluate the biosafety of a chimeric adenoviral vector carrying a green fluorescent protein gene (Ad5/35F-GFP) in a mini-pig model. Results: Transcriptome and secretome analyses of mini-pig leucocytes transduced with Ad5/35F-GFP revealed changes restraining pro-inflammatory processes and cytokine production. No adverse effects were revealed through the clinical, instrumental, laboratory, and histological examinations conducted within a week after the direct or autologous leucocyte-mediated administration of Ad5/35F-GFP to mini-pigs. The decrease in cytokine levels in the blood of experimental animals is also consistent with the in vitro data and confirms the immune tolerance of mini-pigs to Ad5/35F-GFP. Conclusions: Here, we show the safety of Ad5/35F in a mini-pig model and provide evidence that Ad5/35F is a promising vector for gene therapy. These results advance our understanding of vector–host interactions and offer a solid foundation for the clinical application of this vector. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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20 pages, 5586 KiB

Open AccessArticle

Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet

by Daniel C. Anthony, Fay Probert, Anna Gorlova, Jenna Hebert, Daniel Radford-Smith, Zlata Nefedova, Aleksei Umriukhin, Andrey Nedorubov, Raymond Cespuglio, Boris Shulgin, Aleksey Lyundup, Klaus Peter Lesch and Tatyana Strekalova

Biomolecules 2024, 14(8), 884; https://doi.org/10.3390/biom14080884 - 23 Jul 2024

Viewed by 1743

Abstract

The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a “Western diet” (WD), which is high in saturated fats, cholesterol, and sugars, can induce [...] Read more.

The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a “Western diet” (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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21 pages, 360 KiB

Open AccessReview

Psychiatric Disease as a Potential Risk Factor for Dementia: A Narrative Review

by Dawson W. Hedges, Morgan Chase, Thomas J. Farrer and Shawn D. Gale

Brain Sci. 2024, 14(7), 722; https://doi.org/10.3390/brainsci14070722 - 18 Jul 2024

Viewed by 2334

Abstract

Neurodegenerative disease is a major global health problem with 150 million people predicted to have dementia by 2050. Genetic factors, environmental factors, demographics, and some diseases have been associated with dementia. In addition to associations between diseases such as hypertension and cerebrovascular disease [...] Read more.

Neurodegenerative disease is a major global health problem with 150 million people predicted to have dementia by 2050. Genetic factors, environmental factors, demographics, and some diseases have been associated with dementia. In addition to associations between diseases such as hypertension and cerebrovascular disease and dementia, emerging findings associate some psychiatric disorders with incident dementia. Because of the high and increasing global prevalence of dementia and the high worldwide prevalence of psychiatric disorders, the primary objective of this narrative review was to evaluate published findings that evaluate the association between bipolar disorder, depression, anxiety, post-traumatic stress disorder, obsessive–compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia and other psychosis syndromes, and personality disorders and personality traits and incident dementia. Here, we highlight findings indicating possible associations between these psychiatric disorders and subsequent dementia and suggest that some psychiatric disorders may be risk factors for incident dementia. Further research, including more large longitudinal studies and additional meta-analyses, however, is needed to better characterize the associations between psychiatric disorders and incident dementia, to identify possible mechanisms for these putative associations, and to identify risk factors within psychiatric disorders that predispose some people with a psychiatric disorder but not others to subsequent dementia. Additional important questions concern how the treatment of psychiatric disorders might affect the risk of incident dementia. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

20 pages, 5054 KiB

Open AccessArticle

Brain–Bone Crosstalk in a Murine Polytrauma Model Promotes Bone Remodeling but Impairs Neuromotor Recovery and Anxiety-Related Behavior

by Katharina Ritter, Markus Baalmann, Christopher Dolderer, Ulrike Ritz and Michael K. E. Schäfer

Biomedicines 2024, 12(7), 1399; https://doi.org/10.3390/biomedicines12071399 - 24 Jun 2024

Viewed by 1392

Abstract

Traumatic brain injury (TBI) and long bone fractures are a common injury pattern in polytrauma patients and modulate each other’s healing process. As only a limited number of studies have investigated both traumatic sites, we tested the hypothesis that brain–bone polytrauma mutually impacts [...] Read more.

Traumatic brain injury (TBI) and long bone fractures are a common injury pattern in polytrauma patients and modulate each other’s healing process. As only a limited number of studies have investigated both traumatic sites, we tested the hypothesis that brain–bone polytrauma mutually impacts neuro- and osteopathological outcomes. Adult female C57BL/6N mice were subjected to controlled cortical impact (CCI), and/or osteosynthetic stabilized femoral fracture (FF), or sham surgery. Neuromotor and behavioral impairments were assessed by neurological severity score, open field test, rotarod test, and elevated plus maze test. Brain and bone tissues were processed 42 days after trauma. CCI+FF polytrauma mice had increased bone formation as compared to FF mice and increased mRNA expression of bone sialoprotein (BSP). Bone fractures did not aggravate neuropathology or neuroinflammation assessed by cerebral lesion size, hippocampal integrity, astrocyte and microglia activation, and gene expression. Behavioral assessments demonstrated an overall impaired recovery of neuromotor function and persistent abnormalities in anxiety-related behavior in polytrauma mice. This study shows enhanced bone healing, impaired neuromotor recovery and anxiety-like behavior in a brain–bone polytrauma model. However, bone fractures did not aggravate TBI-evoked neuropathology, suggesting the existence of outcome-relevant mechanisms independent of the extent of brain structural damage and neuroinflammation. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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20 pages, 3121 KiB

Open AccessArticle

No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson’s Disease

by Mahvish Faisal, Anna Rusetskaya, Liis Väli, Pille Taba, Ave Minajeva and Miriam A. Hickey

Cells 2024, 13(10), 799; https://doi.org/10.3390/cells13100799 - 8 May 2024

Cited by 2 | Viewed by 1457

Abstract

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems [...] Read more.

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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24 pages, 872 KiB

Open AccessReview

Revolutionizing Ischemic Stroke Diagnosis and Treatment: The Promising Role of Neurovascular Unit-Derived Extracellular Vesicles

by Xiangyu Gao, Dan Liu, Kangyi Yue, Zhuoyuan Zhang, Xiaofan Jiang and Peng Luo

Biomolecules 2024, 14(3), 378; https://doi.org/10.3390/biom14030378 - 20 Mar 2024

Cited by 3 | Viewed by 3425

Abstract

Ischemic stroke is a fatal and disabling disease worldwide and imposes a significant burden on society. At present, biological markers that can be conveniently measured in body fluids are lacking for the diagnosis of ischemic stroke, and there are no effective treatment methods [...] Read more.

Ischemic stroke is a fatal and disabling disease worldwide and imposes a significant burden on society. At present, biological markers that can be conveniently measured in body fluids are lacking for the diagnosis of ischemic stroke, and there are no effective treatment methods to improve neurological function after ischemic stroke. Therefore, new ways of diagnosing and treating ischemic stroke are urgently needed. The neurovascular unit, composed of neurons, astrocytes, microglia, and other components, plays a crucial role in the onset and progression of ischemic stroke. Extracellular vesicles are nanoscale lipid bilayer vesicles secreted by various cells. The key role of extracellular vesicles, which can be released by cells in the neurovascular unit and serve as significant facilitators of cellular communication, in ischemic stroke has been extensively documented in recent literature. Here, we highlight the role of neurovascular unit-derived extracellular vesicles in the diagnosis and treatment of ischemic stroke, the current status of extracellular vesicle engineering for ischemic stroke treatment, and the problems encountered in the clinical translation of extracellular vesicle therapies. Extracellular vesicles derived from the neurovascular unit could provide an important contribution to diagnostic and therapeutic tools in the future, and more studies in this area should be carried out. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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25 pages, 8503 KiB

Open AccessArticle

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

by Diána Martos, Bálint Lőrinczi, István Szatmári, László Vécsei and Masaru Tanaka

Int. J. Mol. Sci. 2024, 25(6), 3394; https://doi.org/10.3390/ijms25063394 - 16 Mar 2024

Cited by 11 | Viewed by 6176

Abstract

The central nervous system (CNS) is the final frontier in drug delivery because of the blood–brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in [...] Read more.

The central nervous system (CNS) is the final frontier in drug delivery because of the blood–brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions, and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain-modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically, SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open-field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 μmol/4 μL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 μmol/4 μL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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26 pages, 1141 KiB

Open AccessReview

Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity

by Simone Battaglia, Chiara Di Fazio, Matteo Mazzà, Marco Tamietto and Alessio Avenanti

Int. J. Mol. Sci. 2024, 25(2), 864; https://doi.org/10.3390/ijms25020864 - 10 Jan 2024

Cited by 24 | Viewed by 3884

Abstract

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, [...] Read more.

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, a ubiquitous aspect of life, influences fear learning and extinction by changing the activity of the amygdala, prefrontal cortex, and hippocampus, leading to enhanced fear responses and/or impaired extinction. Glucocorticoid receptors (GRs) are key to the stress response and show a dual function in fear regulation: while they enhance the consolidation of fear memories, they also facilitate extinction. Accordingly, GR dysregulation is associated with anxiety and mood disorders. Recent advancements in cognitive neuroscience underscore the need for a comprehensive understanding that integrates perspectives from the molecular, cellular, and systems levels. In particular, neuropharmacology provides valuable insights into neurotransmitter and receptor systems, aiding the investigation of mechanisms underlying fear regulation and potential therapeutic targets. A notable player in this context is cortisol, a key stress hormone, which significantly influences both fear memory reconsolidation and extinction processes. Gaining a thorough understanding of these intricate interactions has implications in terms of addressing psychiatric disorders related to stress. This review sheds light on the complex interactions between cognitive processes, emotions, and their neural bases. In this endeavor, our aim is to reshape the comprehension of fear, stress, and their implications for emotional well-being, ultimately aiding in the development of therapeutic interventions. Full article

(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models, from Animals to Humans, from Qualitative to Quantitative Methods, 3rd Edition)

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