-
Scientific Reports Jun 2024Glucose transporter-2 (GLUT2) monitors cellular glucose uptake. Astrocyte GLUT2 controls glucose counterregulatory hormone secretion. In vivo gene silencing and...
Glucose transporter-2 (GLUT2) monitors cellular glucose uptake. Astrocyte GLUT2 controls glucose counterregulatory hormone secretion. In vivo gene silencing and laser-catapult-microdissection tools were used here to investigate whether ventromedial hypothalamic nucleus (VMN) GLUT2 may regulate dorsomedial (VMNdm) and/or ventrolateral (VMNvl) γ-aminobutyric acid (GABA) neurotransmission to control this endocrine outflow in female rats. VMN GLUT2 gene knockdown suppressed or stimulated hypoglycemia-associated glutamate decarboxylase (GAD)1 and GAD2 mRNA expression in VMNdm versus VMNvl GABAergic neurons, respectively. GLUT2 siRNA pretreatment also modified co-expressed transmitter marker gene profiles in each cell population. VMNdm GABA neurons exhibited GLUT2 knockdown-sensitive up-regulated 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) transcripts during hypoglycemia. Hypoglycemic augmentation of VMNvl GABA neuron AMPKα2 was refractory to GLUT2 siRNA. GLUT2 siRNA blunted (VMNdm) or exacerbated (VMNvl) hypoglycemic stimulation of GABAergic neuron steroidogenic factor-1 (SF-1) mRNA. Results infer that VMNdm and VMNvl GABA neurons may exhibit divergent, GLUT2-dependent GABA neurotransmission patterns in the hypoglycemic female rat. Data also document differential GLUT2 regulation of VMNdm versus VMNvl GABA nerve cell SF-1 gene expression. Evidence for intensification of hypoglycemic hypercorticosteronemia and -glucagonemia by GLUT2 siRNA infers that VMN GLUT2 function imposes an inhibitory tone on these hormone profiles in this sex.
Topics: Animals; Female; Rats; Glucose Transporter Type 2; GABAergic Neurons; Ventromedial Hypothalamic Nucleus; Hypoglycemia; Gene Expression Regulation; Glutamate Decarboxylase; Rats, Sprague-Dawley; Glucose; AMP-Activated Protein Kinases; RNA, Small Interfering
PubMed: 38902332
DOI: 10.1038/s41598-024-64708-y -
Scientific Reports Jun 2024Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and...
Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and society. Here, we investigated whether transcranial Direct Current Stimulation (tDCS) applied to two prefrontal cortex regions, the ventromedial prefrontal cortex (vmPFC, anode) and the right dorsolateral prefrontal cortex (DLPFC, cathode) can induce changes in self-reported emotions and to modulate local metabolite concentrations. We employed in vivo quantitative MR Spectroscopy in healthy adult participants and quantified changes in GABA and Glx (glutamate + glutamine) before and after five sessions of tDCS delivered at 2 mA for 20 min (active group) and 1 min (sham group) while participants were engaged in a charitable donation task. In the active group, we observed increased levels of GABA in vmPFC. Glx levels decreased in both prefrontal regions and self-reported happiness increased significantly over time in the active group. Self-reported guiltiness in both active and sham groups tended to decrease. The results indicate that self-reported happiness can be modulated, possibly due to changes in Glx concentrations following repeated stimulation. Therefore, local changes may induce remote changes in the reward network through interactions with other metabolites, previously thought to be unreachable with noninvasive stimulation techniques.
Topics: Humans; Transcranial Direct Current Stimulation; Male; Female; Prefrontal Cortex; Adult; Emotions; Young Adult; gamma-Aminobutyric Acid; Glutamic Acid; Altruism; Glutamine; Magnetic Resonance Spectroscopy; Dorsolateral Prefrontal Cortex
PubMed: 38902321
DOI: 10.1038/s41598-024-64876-x -
Translational Psychiatry Jun 2024Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying...
Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T) and iron concentration (proxied by transverse relaxation time T*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.
Topics: Humans; Depressive Disorder, Major; Magnetic Resonance Imaging; Female; Male; Adult; Prefrontal Cortex; Gyrus Cinguli; Myelin Sheath; Middle Aged; Iron; Case-Control Studies
PubMed: 38902245
DOI: 10.1038/s41398-024-02976-y -
Nature Communications Jun 2024The ability to establish associations between environmental stimuli is fundamental for higher-order brain functions like state inference and generalization. Both the...
The ability to establish associations between environmental stimuli is fundamental for higher-order brain functions like state inference and generalization. Both the hippocampus and orbitofrontal cortex (OFC) play pivotal roles in this, demonstrating complex neural activity changes after associative learning. However, how precisely they contribute to representing learned associations remains unclear. Here, we train head-restrained mice to learn four 'odor-outcome' sequence pairs composed of several task variables-the past and current odor cues, sequence structure of 'cue-outcome' arrangement, and the expected outcome; and perform calcium imaging from these mice throughout learning. Sequence-splitting signals that distinguish between paired sequences are detected in both brain regions, reflecting associative memory formation. Critically, we uncover differential contents in represented associations by examining, in each area, how these task variables affect splitting signal generalization between sequence pairs. Specifically, the hippocampal splitting signals are influenced by the combination of past and current cues that define a particular sensory experience. In contrast, the OFC splitting signals are similar between sequence pairs that share the same sequence structure and expected outcome. These findings suggest that the hippocampus and OFC uniquely and complementarily organize the acquired associative structure.
Topics: Animals; Hippocampus; Prefrontal Cortex; Neurons; Mice; Male; Mice, Inbred C57BL; Association Learning; Cues; Odorants; Memory
PubMed: 38902232
DOI: 10.1038/s41467-024-49652-9 -
Acta Medica Okayama Jun 2024Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was...
Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.
Topics: Animals; Zolpidem; Lipopolysaccharides; Mice; Pyridines; Male; Receptors, GABA-A; Symporters; Reflex, Righting; Hippocampus; K Cl- Cotransporters; Hypnotics and Sedatives; Inflammation; Frontal Lobe
PubMed: 38902210
DOI: 10.18926/AMO/67197 -
ENeuro Jun 2024Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated...
Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic G and G associated G-protein coupled receptor (GPCR) signaling has been shown to affect memory processing, but little is known about the role of cortical astrocytic G-GPCR signaling in remote memory acquisition and the functioning of cortical engram neurons. We assessed this by chemogenetic manipulation of astrocytes in the medial prefrontal cortex (mPFC) of male mice, during either encoding or consolidation of a contextual fear memory, while simultaneously labeling cortical engram neurons. We found that stimulation of astrocytic G signaling during memory encoding and consolidation did not alter remote memory expression. In line with this, the size of the mPFC engram population and the recall-induced reactivation of these neurons was unaffected. Hence, our data indicate that activation of G-GPCR signaling in cortical astrocytes is not sufficient to alter memory performance and functioning of cortical engram neurons.
Topics: Animals; Astrocytes; Male; Prefrontal Cortex; Signal Transduction; Neurons; Fear; Mice, Inbred C57BL; GTP-Binding Protein alpha Subunits, Gs; Mice; Memory; Memory, Long-Term
PubMed: 38902023
DOI: 10.1523/ENEURO.0056-24.2024 -
PloS One 2024Based on the CRISP theory (Content Representation, Intrinsic Sequences, and Pattern completion), we present a computational model of the hippocampus that allows for...
Based on the CRISP theory (Content Representation, Intrinsic Sequences, and Pattern completion), we present a computational model of the hippocampus that allows for online one-shot storage of pattern sequences without the need for a consolidation process. In our model, CA3 provides a pre-trained sequence that is hetero-associated with the input sequence, rather than storing a sequence in CA3. That is, plasticity on a short timescale only occurs in the incoming and outgoing connections of CA3, not in its recurrent connections. We use a single learning rule named Hebbian descent to train all plastic synapses in the network. A forgetting mechanism in the learning rule allows the network to continuously store new patterns while forgetting those stored earlier. We find that a single cue pattern can reliably trigger the retrieval of sequences, even when cues are noisy or missing information. Furthermore, pattern separation in subregion DG is necessary when sequences contain correlated patterns. Besides artificially generated input sequences, the model works with sequences of handwritten digits and natural images. Notably, our model is capable of improving itself without external input, in a process that can be referred to as 'replay' or 'offline-learning', which helps in improving the associations and consolidating the learned patterns.
Topics: Neural Networks, Computer; Models, Neurological; Humans; Neuronal Plasticity; Learning; Hippocampus; Synapses
PubMed: 38900733
DOI: 10.1371/journal.pone.0304076 -
Addiction Biology Jun 2024A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However,...
A growing body of evidence indicates the existence of abnormal local and long-range functional connection patterns in patients with alcohol use disorder (AUD). However, it has yet to be established whether AUD is associated with abnormal interhemispheric and intrahemispheric functional connection patterns. In the present study, we analysed resting-state functional magnetic resonance imaging data from 55 individuals with AUD and 32 healthy nonalcohol users. For each subject, whole-brain functional connectivity density (FCD) was decomposed into ipsilateral and contralateral parts. Correlation analysis was performed between abnormal FCD and a range of clinical measurements in the AUD group. Compared with healthy controls, the AUD group exhibited a reduced global FCD in the anterior and middle cingulate gyri, prefrontal cortex and thalamus, along with an enhanced global FCD in the temporal, parietal and occipital cortices. Abnormal interhemispheric and intrahemispheric FCD patterns were also detected in the AUD group. Furthermore, abnormal global, contralateral and ipsilateral FCD data were correlated with the mean amount of pure alcohol and the severity of alcohol addiction in the AUD group. Collectively, our findings indicate that global, interhemispheric and intrahemispheric FCD may represent a robust method to detect abnormal functional connection patterns in AUD; this may help us to identify the neural substrates and therapeutic targets of AUD.
Topics: Humans; Male; Alcoholism; Magnetic Resonance Imaging; Adult; Brain; Middle Aged; Prefrontal Cortex; Thalamus; Case-Control Studies; Gyrus Cinguli; Brain Mapping; Young Adult
PubMed: 38899438
DOI: 10.1111/adb.13398 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424 -
Brain and Behavior Jun 2024Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as...
BACKGROUND AND AIM
Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well-established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP).
METHODS
We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open-field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)-1β, tumor necrosis factor (TNF), and toll-like receptor 4 (TLR4) in the HIP, were measured.
RESULTS
The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL-1β, TLR4, and TNF, along with a reduction in nitrite levels following resocialization.
CONCLUSION
These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.
Topics: Animals; Social Isolation; Hippocampus; Mice; Male; Stress, Psychological; Depression; Nitrites; Neuroinflammatory Diseases; Behavior, Animal; Interleukin-1beta; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 38898740
DOI: 10.1002/brb3.3604