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PLoS Biology Apr 2024Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive...
Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.
Topics: Animals; Gerbillinae; Neurons; Acoustic Stimulation; Superior Olivary Complex; Sound Localization; Male; Olivary Nucleus; Sound; Female
PubMed: 38683852
DOI: 10.1371/journal.pbio.3002586 -
Alzheimer's & Dementia : the Journal of... Jun 2024Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial...
INTRODUCTION
Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FC) on cortical atrophy across Braak stage regions and its impact on cognition.
METHODS
We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FC with longitudinal atrophy and cognition with and without Aβ moderation.
RESULTS
Cross-sectionally, lower FC was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FC at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FC and subsequent cognitive decline.
DISCUSSION
FC is implicated in Aβ-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD.
HIGHLIGHTS
Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.
Topics: Humans; Locus Coeruleus; Male; Female; Atrophy; Cognitive Dysfunction; Magnetic Resonance Imaging; Aged; Positron-Emission Tomography; Alzheimer Disease; Cross-Sectional Studies; Temporal Lobe; Amyloid beta-Peptides; Longitudinal Studies; Neural Pathways
PubMed: 38676563
DOI: 10.1002/alz.13839 -
International Journal of Molecular... Apr 2024Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity....
Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity. Its mutation causes the autism-like ADNP syndrome (also called the Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders and motor dysfunctions. Similar to the ADNP syndrome, the haploinsufficient mouse shows low synapse density, leading to motor and cognitive ability delays. Moderate physical activity (PA) has several neuroprotective and cognitive benefits, promoting neuronal survival, differentiation, neurogenesis, and plasticity. Until now, no study has investigated the effect of moderate exercise on ADNP expression and distribution in the rat brain. The aim of the current investigation was to study the effects of moderate exercise on the ADNP expression and neuronal activation measured by the microtubule protein β-Tubulin III. In pursuit of this objective, twenty-four rats were selected and evenly distributed into two categories: sedentary control rats and rats exposed to moderate physical activity on a treadmill over a span of 12 weeks. Our results showed that moderate PA increases the expression of ADNP and β-Tubulin III in the dentate gyrus (DG) hippocampal region and cerebellum. Moreover, we found a co-localization of ADNP and β-Tubulin III in both DG and cerebellum, suggesting a direct association of ADNP with adult neuronal activation induced by moderate PA.
Topics: Animals; Male; Rats; Brain; Cerebellum; Dentate Gyrus; Nerve Tissue Proteins; Neurons; Physical Conditioning, Animal; Tubulin; Rats, Wistar
PubMed: 38673966
DOI: 10.3390/ijms25084382 -
International Journal of Molecular... Apr 2024Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs)....
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood-brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
Topics: Animals; Spinocerebellar Ataxias; Peptides; Disease Models, Animal; Dependovirus; Mice; Ataxin-7; Trinucleotide Repeat Expansion; RNA, Small Interfering; Phenotype; Genetic Vectors; Purkinje Cells; Mice, Transgenic; Cerebellum; Humans; Genetic Therapy; Alleles
PubMed: 38673939
DOI: 10.3390/ijms25084354 -
International Journal of Molecular... Apr 2024According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of...
According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response.
Topics: Animals; Dopaminergic Neurons; Male; Mice; Social Behavior; Humans; Clozapine; Raphe Nuclei; Behavior, Animal; Dopamine; Mice, Inbred C57BL
PubMed: 38673899
DOI: 10.3390/ijms25084315 -
International Journal of Molecular... Apr 2024Chronic ethanol exposure often triggers neuroinflammation in the brain's reward system, potentially promoting the drive for ethanol consumption. A main marker of...
Chronic ethanol exposure often triggers neuroinflammation in the brain's reward system, potentially promoting the drive for ethanol consumption. A main marker of neuroinflammation is the microglia-derived monocyte chemoattractant protein 1 (MCP1) in animal models of alcohol use disorder in which ethanol is forcefully given. However, there are conflicting findings on whether MCP1 is elevated when ethanol is taken voluntarily, which challenges its key role in promoting motivation for ethanol consumption. Here, we studied MCP1 mRNA levels in areas implicated in consumption motivation-specifically, the prefrontal cortex, hippocampus, and striatum-as well as in the cerebellum, a brain area highly sensitive to ethanol, of C57BL/6 mice subjected to intermittent and voluntary ethanol consumption for two months. We found a significant increase in MCP1 mRNA levels in the cerebellum of mice that consumed ethanol compared to controls, whereas no significant changes were observed in the prefrontal cortex, hippocampus, or striatum or in microglia isolated from the hippocampus and striatum. To further characterize cerebellar neuroinflammation, we measured the expression changes in other proinflammatory markers and chemokines, revealing a significant increase in the proinflammatory microRNA miR-155. Notably, other classical proinflammatory markers, such as TNFα, IL6, and IL-1β, remained unaltered, suggesting mild neuroinflammation. These results suggest that the onset of neuroinflammation in motivation-related areas is not required for high voluntary consumption in C57BL/6 mice. In addition, cerebellar susceptibility to neuroinflammation may be a trigger to the cerebellar degeneration that occurs after chronic ethanol consumption in humans.
Topics: Animals; Prefrontal Cortex; Mice; Hippocampus; Cerebellum; Male; Corpus Striatum; Mice, Inbred C57BL; Ethanol; Alcohol Drinking; Chemokine CCL2; Neuroinflammatory Diseases; Microglia; Inflammation
PubMed: 38673763
DOI: 10.3390/ijms25084173 -
Biological Research Apr 2024Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia...
BACKGROUND
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.
RESULTS
IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.
CONCLUSIONS
All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.
Topics: Animals; Hyperammonemia; Microglia; Cerebellum; Male; Rats; Receptors, Interleukin-17; Rats, Wistar; Neuroinflammatory Diseases; Interleukin-17; Hepatic Encephalopathy; Signal Transduction; Disease Models, Animal
PubMed: 38671534
DOI: 10.1186/s40659-024-00504-2 -
BMC Medical Genomics Apr 2024Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies,...
BACKGROUND
Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS
The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS
A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS
Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
Topics: Humans; Male; Female; Taiwan; Ciliopathies; Child; Child, Preschool; Mutation; Exome Sequencing; Bardet-Biedl Syndrome; Adolescent; Infant; Abnormalities, Multiple; Retina; Syndrome; Cilia; Eye Abnormalities; Cerebellum; Proteins; Kidney Diseases, Cystic
PubMed: 38671463
DOI: 10.1186/s12920-024-01880-0 -
Brain and Cognition Jun 2024While procedural learning (PL) has been implicated in delayed motor skill observed in developmental coordination disorder (DCD), few studies have considered the impact...
While procedural learning (PL) has been implicated in delayed motor skill observed in developmental coordination disorder (DCD), few studies have considered the impact of co-occurring attentional problems. Furthermore, the neurostructural basis of PL in children remains unclear. We investigated PL in children with DCD while controlling for inattention symptoms, and examined the role of fronto-basal ganglia-cerebellar morphology in PL. Fifty-nine children (6-14 years; n = 19, n = 40) completed the serial reaction time (SRT) task to measure PL. The Attention-Deficit Hyperactivity Disorder Rating Scale-IV was administered to measure inattention symptoms. Structural T1 images were acquired for a subset of participants (n = 10, n = 28), and processed using FreeSurfer. Volume was extracted for the cerebellum, basal ganglia, and frontal regions. After controlling for inattention symptoms, the reaction time profile of controls was consistent with learning on the SRT task. This was not the case for those with DCD. SRT task performance was positively correlated with cerebellar cortical volume, and children with DCD trended towards lower cerebellar volume compared to controls. Children with DCD may not engage in PL during the SRT task in the same manner as controls, with this differential performance being associated with atypical cerebellar morphology.
Topics: Humans; Child; Male; Female; Adolescent; Motor Skills Disorders; Reaction Time; Cerebellum; Learning; Magnetic Resonance Imaging; Attention Deficit Disorder with Hyperactivity; Neuroimaging; Attention; Basal Ganglia; Psychomotor Performance; Motor Skills
PubMed: 38670051
DOI: 10.1016/j.bandc.2024.106160 -
Medicine Apr 2024Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering...
RATIONALE
Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing.
PATIENT CONCERNS AND DIAGNOSIS
A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS.
LESSONS
This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.
Topics: Humans; Male; Adult; Kidney Diseases, Cystic; Cerebellum; Eye Abnormalities; Peroneal Neuropathies; Abnormalities, Multiple; Retina; Magnetic Resonance Imaging
PubMed: 38669389
DOI: 10.1097/MD.0000000000037987