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Molecular Psychiatry Jun 2024Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we...
Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders.
PubMed: 38844534
DOI: 10.1038/s41380-024-02619-0 -
Journal of Neurophysiology Jun 2024The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) requires the blockade of the γ-aminobutyric acid A (GABA) receptor. In these studies...
The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) requires the blockade of the γ-aminobutyric acid A (GABA) receptor. In these studies we examined the effectiveness of the specific GABA receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two commonly used species for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 mM BMI. In contrast, a concentration of 10 μM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable long-term potentiation in the rodent DG and highlight the need to take consideration of the species being sued when choosing concentrations of pharmacological agents to employ for electrophysiological use.
PubMed: 38836296
DOI: 10.1152/jn.00188.2024 -
IBRO Neuroscience Reports Jun 2024The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution...
Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.
The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.
PubMed: 38832089
DOI: 10.1016/j.ibneur.2024.05.005 -
Cognitive Neurodynamics Jun 2024[This corrects the article DOI: 10.1007/s11571-021-09728-4.].
[This corrects the article DOI: 10.1007/s11571-021-09728-4.].
PubMed: 38826649
DOI: 10.1007/s11571-023-09949-9 -
Epilepsia May 2024Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and...
Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.
OBJECTIVE
Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV neurons occur in the hippocampus of MeCP2 mice and whether these morphological changes contribute to epilepsy susceptibility.
METHODS
We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV neurons for structural analysis.
RESULTS
Epilepsy susceptibility was increased in MeCP2 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2 mice. The dendritic complexity in MeCP2 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2 mice.
SIGNIFICANCE
Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.
PubMed: 38819633
DOI: 10.1111/epi.18027 -
Frontiers in Neuroanatomy 2024Hox genes govern rostro-caudal identity along the developing spinal cord, which has a well-defined division of function between dorsal (sensory) and ventral (motor)...
INTRODUCTION
Hox genes govern rostro-caudal identity along the developing spinal cord, which has a well-defined division of function between dorsal (sensory) and ventral (motor) halves. Here we exploit developmental Hoxb8 expression, normally restricted to the dorsal cord below the obex, to genetically label spinal cord-to-brain ("spinofugal") axons.
METHODS
We crossed two targeted (knock-in) and two non-targeted recombinase-expressing lines (Hoxb8-IRES-Cre and Hoxb8-T2AFlpO; Hoxb8-Cre and Hoxb8-FlpO, respectively) with appropriate tdtomato-expressing reporter strains. Serial sectioning, confocal and superresolution microscopy, as well as light-sheet imaging was used to reveal robust labeling of ascending axons and their terminals in expected and unexpected regions.
RESULTS
This strategy provides unprecedented anatomical detail of ascending spinal tracts anterior to the brainstem, and reveals a previously undescribed decussating tract in the ventral hypothalamus (the spinofugal hypothalamic decussating tract, or shxt). The absence of Hoxb8-suppressing elements led to multiple instances of ectopic reporter expression in Hoxb8-Cre mice (retinal ganglion and vomeronasal axons, anterior thalamic nuclei and their projections to the anterior cingulate and retrosplenial cortices and subiculum, and a population of astrocytes at the cephalic flexure) and Hoxb8-FlpO mice (Cajal-Retzius cells of the dentate gyrus, and mesenchymal cells of the choroid plexus). While targeted transgenic lines were similar in terms of known spinofugal projections, Hoxb8-IRES-Cre reporters had an additional projection to the core of the facial motor nucleus, and more abundant Hoxb8-lineage microglia scattered throughout the brain than Hoxb8-T2A-FlpO (or any other) mice, suggesting dysregulated Hoxb8-driven reporter expression in one or both lines.
DISCUSSION
This work complements structural and connectivity atlases of the mouse central nervous system, and provides a platform upon which their reactions to injury or disease can be studied. Ectopic Hoxb8-driven recombinase expression may also be a useful tool to study structure and function of other cell populations in non-targeted lines.
PubMed: 38817241
DOI: 10.3389/fnana.2024.1400015 -
Molecular Neurobiology May 2024The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain... (Review)
Review
The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice.
PubMed: 38816676
DOI: 10.1007/s12035-024-04246-w -
Molecular Neurobiology May 2024Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic...
Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.
PubMed: 38814536
DOI: 10.1007/s12035-024-04252-y -
Shock (Augusta, Ga.) May 2024In preclinical traumatic brain injury (TBI) research, the animal model should be selected based on the research question and outcome measures of interest. Direct side by...
In preclinical traumatic brain injury (TBI) research, the animal model should be selected based on the research question and outcome measures of interest. Direct side by side comparisons of different injury models are essential for informing such decisions. Here, we used immunohistochemistry to compare the outcomes from two common models of TBI, lateral fluid percussion (LFP) and repeated mild weight drop (rmWD) in adult female and male Wistar rats. Specifically, we measured the effects of LFP and rmWD on markers of cerebrovascular and tight junction disruption, neuroinflammation, mature neurons, and perineuronal nets in the cortical site of injury, cortex adjacent to injury, dentate gyrus, and the CA2/3 area of the hippocampus. Animals were randomized into LFP or rmWD groups. On day 1, the LFP group received a craniotomy and on day 4, injury (or sham procedure; randomly assigned). The rmWD animals underwent either injury or isoflurane-only (randomly assigned) on each of those 4 days. Seven days after injury, brains were harvested for analysis. Overall, our observations revealed that the most significant disruptions were evident in response to LFP, followed by craniotomy-only, while rmWD animals showed the least residual changes compared to isoflurane-only controls, supporting consideration of rmWD as a mild injury. LFP led to longer-lasting disruptions, perhaps more representative of moderate TBI. We also report that craniotomy and LFP produced greater disruptions in females relative to males. These findings will assist the field in the selection of animal models based on target severity of post-injury outcomes, and support the inclusion of both sexes and appropriate control groups.
PubMed: 38813916
DOI: 10.1097/SHK.0000000000002395 -
Scientific Reports May 2024Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate...
Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.
Topics: Animals; Male; Female; Dendritic Spines; Mice; Estrous Cycle; CA2 Region, Hippocampal; Sex Characteristics; Neurons
PubMed: 38806649
DOI: 10.1038/s41598-024-62951-x