TY  - JOUR
AB  - The global impact of coronavirus disease 2019 (COVID-19) marked by numerous pandemic peaks is attributed to its high variability and infectious nature, transforming it into a persistent global public health concern. With hundreds of millions of cases reported globally, the illness is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite its initial classification as an acute respiratory illness, recent evidence indicates that lingering effects on various bodily systems, such as cardiovascular, pulmonary, nervous, gastrointestinal (GI), and musculoskeletal, may endure well beyond the acute phase. These persistent manifestations following COVID-19, commonly known as long COVID, have the potential to affect individuals across the entire range of illness severity, with a tendency to be more prevalent in mild to moderate cases. At present, there are no established criteria for diagnosing long COVID. Nonetheless, it is conceptualized as a multi-organ disorder encompassing a diverse array of clinical manifestations. The most common, persistent, and debilitating symptoms of long COVID may be neurological, known as neurological complications of post-acute sequelae of COVID-19 (NC-PASC). More than one-third of individuals with a prior SARS-CoV-2 infection show involvement of both the central nervous system (CNS) and peripheral nervous system (PNS), as evidenced by an approximately threefold higher incidence of neurological symptoms in observational studies. The persistent neurological symptoms of long COVID encompass fatigue, headache, cognitive decline, "brain fog", dysautonomia, neuropsychiatric issues, loss of smell (anosmia), loss of taste (ageusia), and peripheral nerve problems (peripheral neuropathy). Reported pathogenic mechanisms encompass viral persistence and neuro-invasion by SARS-CoV-2, neuroinflammation, autoimmunity, coagulopathy, and endotheliopathy. Raising awareness of potential complications is crucial for preventing and alleviating the long-term effects of long COVID and enhancing the prognosis for affected patients. This review explores the hypothetical pathophysiological mechanisms and pathways of NC-PASC with a sole aim to increase awareness about this crippling disease.
AU  - Saxena, A.*
AU  - Mautner, J.
C1  - 71459
C2  - 56194
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - A disease hidden in plain sight: Pathways and mechanisms of neurological complications of post-acute sequelae of COVID-19 (NC-PASC).
JO  - Mol. Neurobiol.
PB  - Springer
PY  - 2024
SN  - 0893-7648
ER  - 

TY  - JOUR
AB  - The effects of the consumption of high-fat diets (HFD) have been studied to unravel the molecular pathways they are altering in order to understand the link between increased caloric intake, metabolic diseases, and the risk of cognitive dysfunction. The saturated fatty acid, palmitic acid (PA), is the main component of HFD and it has been found increased in the circulation of obese and diabetic people. In the central nervous system, PA has been associated with inflammatory responses in astrocytes, but the effects on neurons exposed to it have not been largely investigated. Given that PA affects a variety of metabolic pathways, we aimed to analyze the transcriptomic profile activated by this fatty acid to shed light on the mechanisms of neuronal dysfunction. In the current study, we profiled the transcriptome response after PA exposition at non-toxic doses in primary hippocampal neurons. Gene ontology and Reactome pathway analysis revealed a pattern of gene expression which is associated with inflammatory pathways, and importantly, with the activation of lipid metabolism that is considered not very active in neurons. Validation by quantitative RT-PCR (qRT-PCR) of Hmgcs2, Angptl4, Ugt8, and Rnf145 support the results obtained by RNAseq. Overall, these findings suggest that neurons are able to respond to saturated fatty acids changing the expression pattern of genes associated with inflammatory response and lipid utilization that may be involved in the neuronal damage associated with metabolic diseases.
AU  - Flores-León, M.*
AU  - Alcaraz, N.*
AU  - Pérez-Domínguez, M.*
AU  - Torres-Arciga, K.*
AU  - Rebollar-Vega, R.*
AU  - De La Rosa Velázquez, I.A.
AU  - Arriaga-Canon, C.*
AU  - Herrera, L.A.*
AU  - Arias, C.*
AU  - González-Barrios, R.*
C1  - 62311
C2  - 50765
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 4639-4651
TI  - Transcriptional profiles reveal deregulation of lipid metabolism and inflammatory pathways in neurons exposed to palmitic acid.
JO  - Mol. Neurobiol.
VL  - 58
IS  - 9
PB  - Springer
PY  - 2021
SN  - 0893-7648
ER  - 

TY  - JOUR
AB  - As part of the -superfamily, B2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three B2-mutant lines Crybb2(O377), Crybb2(Philly), and Crybb2(Aey2) included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.
AU  - Heermann, T.
AU  - Garrett, L.
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
AU  - Hölter, S.M.
C1  - 54475
C2  - 45563
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 4215-4230
TI  - Crybb2 mutations consistently affect Schizophrenia endophenotypes in mice.
JO  - Mol. Neurobiol.
VL  - 56
IS  - 6
PB  - Springer
PY  - 2019
SN  - 0893-7648
ER  - 

TY  - JOUR
AB  - In neuropsychiatric diseases, such as major depression and anxiety, pathogenic vulnerability is partially dictated by a genetic predisposition. The search continues to define this genetic susceptibility and establish new genetic elements as potential therapeutic targets. The fibroblast growth factors (FGFs) could be interesting in this regard. This family of signaling molecules plays important roles in development while also functioning within the adult. This includes effects on aspects of brain function such as neurogenesis and synapse formation. Of this family, Fgf9 is expressed in the adult brain, but its functional role is less well defined. In this study, we examined the role of Fgf9 in different brain functions by analyzing the behavior of Fgf9 (Y162C) mutant mice, an Fgf9 allele without the confounding systemic effects of other Fgf9 genetic models. Here, we show that this mutation caused altered locomotor and exploratory reactivity to novel, mildly stressful environments. In addition, mutants showed heightened acoustic startle reactivity as well as impaired social discrimination memory. Notably, there was a substantial decrease in the level of adult olfactory bulb neurogenesis with no difference in hippocampal neurogenesis. Collectively, our findings indicate a role for the Fgf9 (Y162C) mutation in information processing and perception of aversive situations as well as in social memory. Thus, genetic alterations in Fgf9 could increase vulnerability to developing neuropsychiatric disease, and we propose the Fgf9 (Y162C) mutant mice as a valuable tool to study the predictive etiological aspects.
AU  - Garrett, L.
AU  - Becker, L.
AU  - Rozman, J.
AU  - Puk, O.
AU  - Stöger, T.
AU  - Yildirim, A.Ö.
AU  - Bohla, A.
AU  - Eickelberg, O.
AU  - Hans, W.
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Klopstock, T.*
AU  - Rácz, I.*
AU  - Zimmer, A.*
AU  - Klingenspor, M.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Wurst, W.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
AU  - Hölter, S.M.
C1  - 51501
C2  - 43113
SP  - 4580–4595
TI  - Fgf9Y162C mutation alters information processing and social memory in mice.
JO  - Mol. Neurobiol.
VL  - 55
IS  - 6
PY  - 2017
SN  - 0893-7648
ER  - 

TY  - JOUR
AB  - Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons (Srf;CaMKIIa-CreERT2) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in Srf mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms.
AU  - Zimprich, A.
AU  - Mroz, G.*
AU  - Meyer Zu Reckendorf, C.*
AU  - Anastasiadou, S.*
AU  - Förstner, P.*
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Becker, L.
AU  - Rozman, J.
AU  - Prehn, C.
AU  - Rathkolb, B.
AU  - Moreth, K.
AU  - Wurst, W.
AU  - Klopstock, T.*
AU  - Klingenspor, M.*
AU  - Adamski, J.
AU  - Wolf, E.*
AU  - Bekeredjian, R.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Knöll, B.*
C1  - 50132
C2  - 42053
CY  - Totowa
SP  - 8242–8262
TI  - Serum response factor (SRF) ablation interferes with acute stress-associated immediate and long-term coping mechanisms.
JO  - Mol. Neurobiol.
VL  - 54
IS  - 10
PB  - Humana Press Inc
PY  - 2016
SN  - 0893-7648
ER  -